Durable multi-layer high strength polymer composite suitable for implant and articles produced therefrom

ABSTRACT

A thin, biocompatible, high-strength, composite material is disclosed that is suitable for use in various implanted configurations. The composite material maintains flexibility in high-cycle flexural applications, making it particularly applicable to high-flex implants such as heart pacing lead or heart valve leaflet. The composite material includes at least one porous expanded fluoropolymer layer and an elastomer substantially filling substantially all of the pores of the porous expanded fluoropolymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This instant application is a continuation-in-part of co-pending U.S.patent application Ser. No. 13/485,823, filed May 31, 2012, which is acontinuation-in-part application of co-pending U.S. patent applicationSer. No. 13/078,774 filed Apr. 1, 2011, wherein U.S. patent applicationSer. No. 13/485,823 claims priority to Provisional Application Ser. No.61/492,324 filed Jun. 1, 2011, all of which are herein incorporated byreference in their entirety.

BACKGROUND

1. Field

This disclosure relates to materials used in medical implants. Moreparticularly, the disclosure relates to a biocompatible materialsuitable for use in high-cycle flexural applications includingartificial heart valves.

2. Background

Artificial heart valves preferably should last at least ten years invivo. To last that long, artificial heart valves should exhibitsufficient durability for at least four hundred million cycles or more.The valves, and more specifically heart valve leaflets, must resiststructural degradation including the formation of holes, tears, and thelike, as well as adverse biological consequences including calcificationand thrombosis.

Fluoropolymers, such as expanded and non-expanded forms ofpolytetrafluoroethylene (PTFE), modified PTFE, and copolymers of PTFE,offer a number of desirable properties, including excellent inertnessand superior biocompatibility, and, therefore make ideal candidatematerials. PTFE and expanded PTFE (ePTFE) have been used to create heartvalve leaflets. It has been shown, however, that PTFE stiffens withrepeated flexure, which can lead to unacceptable flow performance.Failure due to formation of holes and tears in the material has alsobeen observed. A variety of polymeric materials have previously beenemployed as prosthetic heart valve leaflets. Failure of these leafletsdue to stiffening and hole formation occurred within two years ofimplant. Efforts to improve leaflet durability by thickening theleaflets resulted in unacceptable hemodynamic performance of the valves,that is, the pressure drop across the open valve was too high.

As such, it remains desirable to provide a biocompatible artificialheart valve design that lasts at least ten years in vivo by exhibitingsufficient durability for at least about four hundred million cycles offlexure or more.

SUMMARY

According to embodiments, an implantable article is provided forregulating blood flow direction in a human patient. Such an article mayinclude, but is not limited to, a cardiac valve or a venous valve

In one embodiment, the implantable article includes a leaflet comprisinga composite material with at least one fluoropolymer layer having aplurality of pores and an elastomer present in substantially all of thepores of the at least one fluoropolymer layer, wherein the compositematerial comprises less than about 80% fluoropolymer by weight.

In other exemplary embodiments, the implantable article includes aleaflet having a thickness and formed from a composite material havingmore than one fluoropolymer layer having a plurality of pores and anelastomer present in substantially all of the pores of the more than onefluoropolymer layer, wherein the leaflet has a ratio of leafletthickness (μm) to number of layers of fluoropolymer of less than about5.

In other exemplary embodiments, the implantable article includes asupport structure; a leaflet supported on the support structure, theleaflet having a thickness and formed from a composite material havingmore than one fluoropolymer layer having a plurality of pores and anelastomer present in substantially all of the pores of the more than onefluoropolymer layer, wherein the leaflet has a ratio of leafletthickness (μm) to number of layers of fluoropolymer of less than about5.

In other exemplary embodiments, the implantable article includes aleaflet cyclable between a closed configuration for substantiallypreventing blood flow through the implantable article and an openconfiguration allowing blood flow through the implantable article. Theleaflet is formed from a plurality of fluoropolymer layers and having aratio of leaflet thickness (μm) to number of layers of fluoropolymer ofless than about 5. The leaflet maintains substantially unchangedperformance after actuation of the leaflet at least 40 million cycles.

In other exemplary embodiments, the implantable article includes aleaflet cyclable between a closed configuration for substantiallypreventing blood flow through the implantable article and an openconfiguration allowing blood flow through the implantable article. Theimplantable article also includes a cushion member located between atleast a portion of the support structure and at least a portion of theleaflet, wherein the cushion member is formed from a plurality offluoropolymer layers and having a ratio of leaflet thickness (μm) tonumber of layers of fluoropolymer of less than about 5. The leafletmaintains substantially unchanged performance after actuation of theleaflet at least 40 million cycles.

In exemplary embodiments, a method is provided for forming a leaflet ofan implantable article for regulating blood flow direction in a humanpatient, which includes the steps of: providing a composite materialhaving more than one fluoropolymer layer having a plurality of pores andan elastomer present in substantially all of the pores of the more thanone fluoropolymer layer; and bringing more than one layer of thecomposite material into contact with additional layers of the compositematerial by wrapping a sheet of the composite material with a startingand ending point defined as an axial seam adhered to itself.

In exemplary embodiments, an implantable article is provided forregulating blood flow direction in a human patient, which includes apolymeric leaflet having a thickness of less than about 100 μm.

In another embodiment, the implantable article includes a generallyannular shaped support structure having a first end and an oppositesecond end. The first end of the support structure has a longitudinallyextending post. A sheet of leaflet material extends along an outerperiphery of the support structure and forms first and second leafletsextending along on opposite sides of the post. A cushion member iscoupled to the post and provides a cushion between the post and theleaflets to minimize stress and wear on the leaflets as the leafletscycle between open and closed positions.

According to an embodiment, a valve is provided for regulating bloodflow direction. In an embodiment, the valve includes a leafletcomprising a composite material with at least one fluoropolymer membranecomprising fibrils wherein a diameter of the majority of the fibrils isless than about 1 μm, the space between the fibrils defining pores, theelastomer being disposed in substantially all of the pores.

In another embodiment, the valve includes a support structure and atleast one leaflet being supported on the support structure and movablebetween open and closed positions. Each leaflet includes a compositematerial comprising at least one fluoropolymer membrane and anelastomer. The at least one fluoropolymer membrane comprises fibrilswherein a diameter of the majority of the fibrils is less than about 1μm. The space between the fibrils define pores. The elastomer isdisposed in substantially all of the pores.

In another embodiment, the valve includes a support structure and atleast one leaflet supported on the support structure and movable betweenopen and closed positions. Each leaflet includes a composite materialcomprising at least one fluoropolymer membrane and an elastomer. The atleast one fluoropolymer membrane comprises pores with the elastomerpresent in substantially all of the pores. The composite materialcomprises fluoropolymer membrane by weight in the range of about 10% to90%.

In another embodiment, the valve includes a support structure and atleast one leaflet supported on the support structure and movable betweenopen and closed positions. Each leaflet includes a composite materialcomprising at least one fluoropolymer membrane and an elastomer. The atleast one fluoropolymer membrane comprises pores having a pore size lessthan about 5 μm with the elastomer present in substantially all of thepores.

In another embodiment, a method of forming a leaflet of a prostheticheart valve is provided. The method comprises providing a compositematerial comprising at least one fluoropolymer membrane and anelastomer, the at least one fluoropolymer membrane comprising fibrilswherein a diameter of the majority of the fibrils is less than about 1μm, the space between the fibrils defining pores, the elastomer beingdisposed in substantially all of the pores; bringing more than one layerof the composite material into contact with additional layers of thecomposite material; and bonding the layers of composite materialtogether.

In another embodiment, a method of forming a prosthetic heart valveincluding leaflets is provided. The method comprises: providing agenerally annular support structure; providing a composite materialcomprising at least one fluoropolymer membrane and an elastomer, the atleast one fluoropolymer membrane comprising fibrils wherein a diameterof the majority of the fibrils is less than about 1 μm, the spacebetween the fibrils defining pores, the elastomer being disposed insubstantially all of the pores; wrapping the composite material aboutthe support structure bringing more than one layer of the compositematerial into contact with additional layers of the composite material;and bonding the layers of composite material to itself and to thesupport structure.

In another embodiment, a method of forming a leaflet of a prostheticheart valve is provided. The method comprises providing a compositematerial comprising at least one fluoropolymer membrane and anelastomer, the at least one fluoropolymer membrane comprising fibrils,the space between the fibrils defining pores that have a pore size ofless than about 5 μm, the elastomer being disposed in substantially allof the pores; bringing more than one layer of the composite materialinto contact with additional layers of the composite material; andbonding the layers of composite material together.

In another embodiment, a method of forming a prosthetic heart valveincluding leaflets is provided. The method comprises: providing agenerally annular support structure; providing a composite materialcomprising at least one fluoropolymer membrane and an elastomer, the atleast one fluoropolymer membrane comprising fibrils, the space betweenthe fibrils defining pores that have a pore size of less than about 5μm, the elastomer being disposed in substantially all of the pores;wrapping the composite material about the support structure bringingmore than one layer of the composite material into contact withadditional layers of the composite material; and bonding the layers ofcomposite material to itself and to the support structure.

In another embodiment, the valve includes a generally annular shapedsupport structure having a first end and a second end opposite the firstend. The second end comprises a plurality of posts extendinglongitudinally therefrom. A sheet of composite material extends frompost to post wherein leaflets are defined by the composite material thatis between the posts. In an embodiment, a cushion member is coupled tothe post and provides a cushion between the post and the leaflets tominimize stress and wear on the leaflets as the leaflets cycle betweenopen and closed positions.

In another embodiment, the valve includes a support structure includinga leaflet support frame having a plurality of substantiallyparabolically shaped top edges and posts, and a leaflet supported oneach parabolically shaped top edge and posts. Each leaflet defines afree edge not coupled to the support structure. Each leaflet is movablebetween open and closed positions. Each leaflet includes at least twolayers of a composite material comprising more than one fluoropolymerlayer having a plurality of pores and an elastomer present insubstantially all of the pores of the more than one fluoropolymer layer.At least one layer of the at least two layers of a composite material iscoupled to an inner surface of the support structure and at least onelayer of the at least two layers of a composite material is coupled toan outer surface of the support structure.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a furtherunderstanding of the invention and are incorporated in and constitute apart of this specification, illustrate exemplary embodiments of theinvention, and together with the description serve to explain theprinciples of the invention.

FIGS. 1A, 1B, 1C, and 1D are front, side and top elevational views, anda perspective view, respectively, of a tool for forming a heart valveleaflet, in accordance with an embodiment;

FIG. 2A is a perspective view of a cushion pad being stretched over aleaflet tool, in accordance with an embodiment;

FIG. 2B is a perspective view of a release layer being stretched overthe cushion pad covered leaflet tool in FIG. 2A, in accordance with anembodiment;

FIGS. 3A, 3B and 3C are top, side and front elevational viewsillustrating a step in the formation of a valve leaflet, in which theleaflet tool covered by the cushion pad and release layer (shown inFIGS. 2A and 2B, respectively) is positioned over a composite materialfor cutting and further assembly, in accordance with an embodiment;

FIG. 4 is a top elevational view of a tri-leaflet assembly prior tocutting excess leaflet material, in accordance with an embodiment;

FIG. 5A is a perspective view of the tri-leaflet assembly and a basetool, in accordance with an embodiment;

FIG. 5B is a perspective view of the tri-leaflet assembly and base toolaligned and assembled to form a base tool assembly, in accordance withan embodiment;

FIG. 6A is a flattened plane view of a stent frame or support structure,in accordance with an embodiment;

FIG. 6B is a flattened plane view of the support structure covered in apolymer coating, in accordance with an embodiment;

FIGS. 7A, 7B and 7C are scanning electron micrograph images of expandedfluoropolymer membranes used to form the valve leaflets, in accordancewith an embodiment;

FIG. 8 is a perspective view of a valve assembly, in accordance with anembodiment;

FIGS. 9A and 9B are top elevational views of the heart valve assembly ofFIG. 8 shown illustratively in closed and open positions, respectively,in accordance with an embodiment;

FIG. 10 is a graph of measured outputs from a heart flow pulseduplicator system used for measuring performance of the valveassemblies;

FIGS. 11A and 11B are a graph and data chart of measured outputs from ahigh rate fatigue tester used for measuring performance of the valveassemblies;

FIGS. 12A and 12B are graphs of measured outputs from the heart flowpulse duplicator system taken while testing valve assemblies accordingto and embodiment at zero cycles and after about 207 million cycles,respectively;

FIGS. 13A and 13B are graphs of measured outputs from the heart flowpulse duplicator system taken while testing valve assemblies inaccordance with embodiments at about 79 million cycles and after about198 million cycles, respectively;

FIG. 14 is a perspective view of a mandrel for manufacturing a heartvalve assembly, in accordance with an embodiment;

FIG. 15 is a perspective view of a valve frame for a heart valve, inaccordance with an embodiment;

FIG. 16 is a perspective view of the valve frame of FIG. 15 nestedtogether with the mandrel FIG. 14, in accordance with an embodiment;

FIG. 17 is a perspective view of a molded valve, in accordance with anembodiment;

FIG. 18 is a perspective view of a molded valve, showing an attachmentmember for reinforcing a bond between adjacent valve leaflets and a postof a valve frame, in accordance with an embodiment;

FIG. 19 is a perspective view of a valve frame, in accordance with anembodiment;

FIG. 20 is a perspective view of the valve frame of FIG. 19 with poststhat are cushion-wrapped, in accordance with an embodiment;

FIG. 21 is a perspective view of a stereolithography-formed mandrel, inaccordance with an embodiment;

FIG. 22 is a perspective view of the cushion-wrapped valve frame of FIG.20 mounted onto the mandrel of FIG. 21, in accordance with anembodiment;

FIG. 23 is a perspective view of a valve having valve leaflets coupledto and supported on the cushion-wrapped valve frame of FIG. 20, inaccordance with an embodiment

FIG. 24 is a perspective view of a non-collapsible stent frame orsupport structure, in accordance with an embodiment;

FIG. 25 is a perspective view of a laminated stent frame, in accordancewith an embodiment;

FIG. 26A is a perspective view of the tri-leaflet assembly, base tool,stent frame encapsulated within a composite strain relief and sewingring, in accordance with an embodiment;

FIG. 26B is a perspective view of a tri-leaflet assembly, in accordancewith an embodiment;

FIG. 27 is a perspective view of a valve, in accordance with anembodiment;

FIG. 28 is a perspective view of a valve and fixture, in accordance withan embodiment;

FIG. 29 is a perspective view of a valve, fixture, and press, inaccordance with an embodiment;

FIG. 30 is a perspective view of a completed valve, in accordance withan embodiment;

FIG. 31 is a perspective view of a non-collapsible stent frame orsupport structure of FIG. 24 with a cushion member covering a perimeterof the structure, in accordance with an embodiment;

FIG. 32 is a perspective view of a completed valve having leafletscoupled to and supported on a frame or support structure with a cushionmember covering a perimeter of the support structure, a strain relief,and a sewing flange, in accordance with an embodiment;

FIG. 33A is a perspective view of a collapsible stent frame or supportstructure of FIG. 6A with a cushion member covering the regions of thestructure to which leaflets are attached, in accordance with anembodiment;

FIG. 33B is a flattened plane view of the support structure of FIG. 6Awith a polymer coating encapsulating the cushion members, in accordancewith an embodiment;

FIG. 34 is a perspective view of the collapsible stent frame and cushionmembers of FIGS. 33A and 33B with leaflet material wrapped as cylinderover the exterior of the frame with three axial slits, in accordancewith an embodiment;

FIG. 35 is a perspective view of FIG. 34 with three tabs of leafletmaterial internalized to stent frame through individual openings, inaccordance with an embodiment;

FIG. 36 is a perspective view of a completed valve having leafletscoupled to and supported on a collapsible frame with a cushion member atleaflet attachment sites of structure and a strain relief, in accordancewith an embodiment;

FIG. 37 is a graph of leaflet thickness and numbers of layers for asingle composite material, in accordance with embodiments;

FIG. 38 is a graph comparing the leaflet thickness and numbers of layersfor two different composite materials, in accordance with embodiments;

FIG. 39 is a sample graph of leaflet thickness and number of layers withboundaries defined for hydrodynamic performance, minimum number oflayers, minimum strength, maximum composite thickness, and maximumpercentage of fluoropolymer, in accordance with embodiments;

FIG. 40 is a graph of leaflet thickness and number of layers withboundaries defined for hydrodynamic performance, minimum number oflayers, minimum strength, maximum composite thickness, and maximumpercentage of fluoropolymer for the leaflet configurations of Examples1, 2, 3, A, B, 4A, 4B, 4C, 5, 6, 7, & 8, in accordance with embodiments;

FIG. 41A is a graph of leaflet thickness and number of layers depictinggeneral trends of improved durability observed during accelerated weartesting;

FIG. 41B is a graph of leaflet thickness and number of layers depictinggeneral trends of reduced durability observed during accelerated weartesting;

FIG. 42 is a graph of hydrodynamic performance data (EOA and regurgitantfraction) comparing two valves, in accordance with embodiments;

FIG. 43 is Table 4, which is a table of performance data for examplevalves, in accordance with embodiments; and

FIG. 44 is Table 6, which is a table of performance data for examplevalves, in accordance with embodiments.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Definitions for some terms used herein are provided below in theAppendix.

The embodiments presented herein address a long-felt need for a materialthat meets the durability and biocompatibility requirements ofhigh-cycle flexural implant applications, such as heart valve leaflets.It has been observed that heart valve leaflets formed from porousfluoropolymer materials or, more particularly, from ePTFE containing noelastomer suffer from stiffening in high-cycle flex testing and animalimplantation.

In one embodiment, described in greater detail below, the flexuraldurability of porous fluoropolymer heart valve leaflets wassignificantly increased by adding a relatively high-percentage ofrelatively lower strength elastomer to the pores. Optionally, additionallayers of the elastomer may be added between the composite layers.Surprisingly, in embodiments wherein porous fluoropolymer membranes areimbibed with elastomer the presence of the elastomer increased overallthickness of the leaflet, the resulting increased thickness of thefluoropolymer members due to the addition of the elastomer did nothinder or diminish flexural durability. Further, after reaching aminimum percent by weight of elastomer, it was found that fluoropolymermembers in general performed better with increasing percentages ofelastomer resulting in significantly increased cycle lives exceeding 40million cycles in vitro, as well as by showing no signs of calcificationunder certain controlled laboratory conditions.

A material according to one embodiment includes a composite materialcomprising an expanded fluoropolymer membrane and an elastomericmaterial. It should be readily appreciated that multiple types offluoropolymer membranes and multiple types of elastomeric materials canbe combined while within the spirit of the present embodiments. Itshould also be readily appreciated that the elastomeric material caninclude multiple elastomers, multiple types of non-elastomericcomponents, such as inorganic fillers, therapeutic agents, radiopaquemarkers, and the like while within the spirit of the presentembodiments.

In one embodiment, the composite material includes an expandedfluoropolymer material made from porous ePTFE membrane, for instance asgenerally described in U.S. Pat. No. 7,306,729.

The expandable fluoropolymer, used to form the expanded fluoropolymermaterial described, may comprise PTFE homopolymer. In alternativeembodiments, blends of PTFE, expandable modified PTFE and/or expandedcopolymers of PTFE may be used. Non-limiting examples of suitablefluoropolymer materials are described in, for example, U.S. Pat. No.5,708,044, to Branca, U.S. Pat. No. 6,541,589, to Baillie, U.S. Pat. No.7,531,611, to Sabol et al., U.S. patent application Ser. No. 11/906,877,to Ford, and U.S. patent application Ser. No. 12/410,050, to Xu et al.

The expanded fluoropolymer of the present embodiments may comprise anysuitable microstructure for achieving the desired leaflet performance.In one embodiment, the expanded fluoropolymer may comprise amicrostructure of nodes interconnected by fibrils, such as described inU.S. Pat. No. 3,953,566 to Gore. In one embodiment, the microstructureof an expanded fluoropolymer membrane comprises nodes interconnected byfibrils as shown in the scanning electron micrograph image in FIG. 7A.The fibrils extend from the nodes in a plurality of directions, and themembrane has a generally homogeneous structure. Membranes having thismicrostructure may typically exhibit a ratio of matrix tensile strengthin two orthogonal directions of less than 2, and possibly less than 1.5.It is anticipated that expanded fluoropolymer membrane may have a meanflow pore sizes of less than about 5 μm, less than about 1 μm, and lessthan about 0.10 μm, in accordance with embodiments. It is anticipatedthat expanded fluoropolymer membrane may have substantially all thefibrils having a diameter of less than about 1 μm.

In another embodiment, the expanded fluoropolymer may have amicrostructure of substantially only fibrils, such as, for example,depicted in FIGS. 7B and 7C, as is generally taught by U.S. Pat. No.7,306,729, to Bacino. FIG. 7C is a higher magnification of the expandedfluoropolymer membrane shown in FIG. 7B, and more clearly shows thehomogeneous microstructure having substantially only fibrils. Theexpanded fluoropolymer membrane having substantially only fibrils asdepicted in FIGS. 7B and 7C, may possess a high surface area, such asgreater than about 20 m²/g, or greater than about 25 m²/g, and in someembodiments may provide a highly balanced strength material having aproduct of matrix tensile strengths in two orthogonal directions of atleast 1.5×10⁵ MPa², and/or a ratio of matrix tensile strengths in twoorthogonal directions of less than 2, and possibly less than 1.5. It isanticipated that expanded fluoropolymer membrane may have a mean flowpore sizes of less than about 5 μm, less than about 1 μm, and less thanabout 0.10 μm, in accordance with embodiments. It is anticipated thatexpanded fluoropolymer membrane may have substantially all the fibrilshaving a diameter of less than about 1 μm.

It is appreciated that expanded fluoropolymer membranes disclosed inembodiments provided herein may alternatively be differentiated fromother structures such as fabrics, knits and fiber windings, by lookingat the fibril diameter of the material. Embodiments of expandedfluoropolymer membranes provided herein contain a majority of fibrilshaving a diameter that is less than about 1 μm. Other embodiments ofexpanded fluoropolymer membranes provided herein contain a majority offibrils having a diameter that is less than about 0.1 μm. Theembodiments provided herein recognize that a membrane comprising fibrilsthe majority of which are less than about 1 μm to beyond less than about0.1 μm provide a significant improvement to, at least, but not limitedto, the durability and lifetime of the prosthetic heart valve when usedas leaflet material.

It is appreciated that the structure of the expanded fluoropolymermembranes disclosed in embodiments provided herein, may bedifferentiated from other structures such as fabrics, knits and fiberwindings, by looking at the specific surface area of the material.Embodiments of expanded fluoropolymer membranes provided herein have aspecific surface area of greater than about 4.0 m²/cc. In accordancewith other embodiments of expanded fluoropolymer membranes providedherein have a specific surface area of greater than about 10.0 m²/cc.The embodiments provided herein appreciate that a expanded fluoropolymermembrane having a specific surface area of greater than about 4.0 tomore than about 60 m²/cc provide a significant improvement to, at least,but not limited to, the durability and lifetime of the heart valve whenused as leaflet material.

The expanded fluoropolymer of the present embodiments may be tailored tohave any suitable thickness and mass to achieve the desired leafletperformance. In some cases, it may be desirable to use a very thinexpanded fluoropolymer membrane having a thickness less than about 1.0μm. In other embodiments, it may be desirable to use an expandedfluoropolymer membrane having a thickness greater than about 0.1 μm andless than about 20 μm. The expanded fluoropolymer membranes can possessa specific mass less than about 1 g/m² to greater than about 50 g/m².

Membranes according to embodiments can have matrix tensile strengthsranging from about 50 MPa to about 400 MPa or greater, based on adensity of about 2.2 g/cm³ for PTFE.

Additional materials may be incorporated into the pores or within thematerial of the membranes or in between the layers of the membranes toenhance desired properties of the leaflet. Composites according to oneembodiment can include fluoropolymer membranes having thicknessesranging from about 500 μm to less than about 0.3 μm.

The expanded fluoropolymer membrane combined with elastomer provides theelements of the present embodiments with the performance attributesrequired for use in high-cycle flexural implant applications, such asheart valve leaflets, in at least several significant ways. For example,the addition of the elastomer improves the fatigue performance of theleaflet by eliminating or reducing the stiffening observed withePTFE-only materials. In addition, it reduces the likelihood that thematerial will undergo permanent set deformation, such as wrinkling orcreasing, that could result in compromised performance. In oneembodiment, the elastomer occupies substantially all of the pore volumeor space within the porous structure of the expanded fluoropolymermembrane. In another embodiment the elastomer is present insubstantially all of the pores of the at least one fluoropolymer layer.Having elastomer substantially filling the pore volume or present insubstantially all of the pores reduces the space in which foreignmaterials can be undesirably incorporated into the composite. An exampleof such foreign material is calcium. If calcium becomes incorporatedinto the composite material, as used in a heart valve leaflet, forexample, mechanical damage can occur during cycling, thus leading to theformation of holes in the leaflet and degradation in hemodynamics.

In one embodiment, the elastomer that is combined with the ePTFE is athermoplastic copolymer of tetrafluoroethylene (TFE) and perfluoromethylvinyl ether (PMVE), such as described in U.S. Pat. No. 7,462,675. Asdiscussed above, the elastomer is combined with the expandedfluoropolymer membrane such that the elastomer occupies substantiallyall of the void space or pores within the expanded fluoropolymermembrane. This filling of the pores of the expanded fluoropolymermembrane with elastomer can be performed by a variety of methods. In oneembodiment, a method of filling the pores of the expanded fluoropolymermembrane includes the steps of dissolving the elastomer in a solventsuitable to create a solution with a viscosity and surface tension thatis appropriate to partially or fully flow into the pores of the expandedfluoropolymer membrane and allow the solvent to evaporate, leaving thefiller behind.

In another embodiment, a method of filling the pores of the expandedfluoropolymer membrane includes the steps of delivering the filler via adispersion to partially or fully fill the pores of the expandedfluoropolymer membrane;

In another embodiment, a method of filling the pores of the expandedfluoropolymer membrane includes the steps of bringing the porousexpanded fluoropolymer membrane into contact with a sheet of theelastomer under conditions of heat and/or pressure that allow elastomerto flow into the pores of the expanded fluoropolymer membrane.

In another embodiment, a method of filling the pores of the expandedfluoropolymer membrane includes the steps of polymerizing the elastomerwithin the pores of the expanded fluoropolymer membrane by first fillingthe pores with a prepolymer of the elastomer and then at least partiallycuring the elastomer.

After reaching a minimum percent by weight of elastomer, the leafletsconstructed from fluoropolymer materials or ePTFE generally performedbetter with increasing percentages of elastomer resulting insignificantly increased cycle lives. In one embodiment, the elastomercombined with the ePTFE is a thermoplastic copolymer oftetrafluoroethylene and perfluoromethyl vinyl ether, such as describedin U.S. Pat. No. 7,462,675, and other references that would be known tothose of skill in the art. For instance, in another embodiment shown inExample 1, a leaflet was formed from a composite of 53% by weight ofelastomer to ePTFE and was subjected to cycle testing. Some stiffeningwas observed by around 200 million test cycles, though with only modesteffect on hydrodynamics. When the weight percent of elastomer was raisedto about 83% by weight, as in the embodiment of Example 2, no stiffeningor negative changes in hydrodynamics were observed at about 200 millioncycles. In contrast, with non-composite leaflets, i.e. all ePTFE with noelastomer, as in the Comparative Example B, severe stiffening wasapparent by 40 million test cycles. As demonstrated by these examples,the durability of porous fluoropolymer members can be significantlyincreased by adding a relatively high-percentage of relatively lowerstrength elastomer to the pores of the fluoropolymer members. The highmaterial strength of the fluoropolymer membranes also permits specificconfigurations to be very thin.

Other biocompatible polymers which may be suitable for use inembodiments may include but not be limited to the groups of urethanes,silicones (organopolysiloxanes), copolymers of silicon-urethane,styrene/isobutylene copolymers, polyisobutylene,polyethylene-co-poly(vinyl acetate), polyester copolymers, nyloncopolymers, fluorinated hydrocarbon polymers and copolymers or mixturesof each of the foregoing.

Leaflets constructed from a composite material comprising less thanabout 55% fluoropolymer by weight can be assembled in a variety ofconfigurations based on desired laminate or leaflet thickness and numberof layers of composite. The thickness of the composite is directlyrelated to the percentage of fluoropolymer by weight and membranethickness. Using a range of membrane thickness from about 300 nm to morethan 3,556 nm and a range of percentage of fluoropolymer by weight from10 to 55, for example, allowed the formation of composite thicknessesranging from 0.32 μm to more than about 13 μm.

The relationship between the leaflet thickness and number of compositelayers is shown illustratively in a graph in FIG. 37, wherein twoleaflet configurations, indicated as A and B, are shown. In oneembodiment, these configurations A and B may be constructed from asingle composite. In another embodiment, there may be a generally linearrelationship between leaflet thickness and number of layers, whereinY=mX; in which Y=leaflet thickness, m=slope, and X=number of layers. Theslope (m) or ratio of leaflet thickness to number of layers is equal tothe composite thickness. Therefore, doubling the number of layers from20 to 40 for configurations A and B, for example, has the result ofdoubling the thickness from 40 μm to 80 μm. It should be appreciatedthat the slope of the line or even the shape of the graph of leafletthickness versus number of composite layers can vary depending on theamount of elastomer between the layers and the uniformity of the layers.

When the percentage of fluoropolymer by weight for the same membrane isreduced, the thickness of the composite is increased. As shown in FIG.38, this increase in composite thickness is indicated by the increasedslope of the dotted line relative to the solid line from the previousembodiment. In the embodiment illustrated by the dotted line, areduction of the percentage of fluoropolymer by weight for the samemembrane by about half results in about an increase in thickness of thecomposite by about two, which is reflected in the increased slope of thedotted line. Therefore, a leaflet as depicted by configuration C in FIG.38 can either have the same number of layers as configuration A or thesame leaflet thickness as configuration B by varying the percentage offluoropolymer by weight.

In determining what configurations of percent fluoropolymer by weight,composite thickness, and number of layers influenced both hydrodynamicas well as durability performance, boundaries were observed, as bestshown by the graph in FIG. 39. There are five boundaries that generallydefine suitable leaflet configurations that have been observed thus far.The first boundary is defined by acceptable hydrodynamic performance setforth by ISO guidance document for cardiovascular implants (5840:2005)defining limits of EOA and regurgitant fraction for a given valve size.Typically, leaflets with a thickness greater than about 100 μm formedfrom these composites perform near these limits of acceptability. Thesecond boundary is a minimum number of layers (10) as observed bydurability failures further illustrated by the examples provided.Similarly, the third boundary is a maximum ratio of leaflet thickness tonumber of layers or composite thickness of 5 μm. Generally, low layernumbers built from thick composites performed poorly when compared tohigh layer numbers of either the same percent fluoropolymer by weightand leaflet thickness. The fourth boundary is defined by the minimumnumber of layers of a given composite which is determined by thestrength required to resist fluoropolymer creep during hydrodynamicloading of the leaflet when the valve is closed during the cardiaccycle. The strength of the laminate is measured by a dome burst test,where typically a burst pressure of least 207 KPa is required to ensurethe leaflets maintain their shape and function. The fifth boundary isdefined by the maximum percent fluoropolymer by weight (55%) required tosignificantly increase cyclic durability. In FIG. 40, a graphillustrating these boundaries is shown with the leaflet configurationsof all the examples provided to further illustrate these discoveries.

The maximum number of layers of a given composite may be determined bythe desired leaflet thickness. It has been observed that as leafletthickness increases, the hydrodynamic performance behavior for a givenvalve geometry decreases while the bending character improves.“Hydrodynamic performance” generally refers to the combination of EOAand regurgitant fraction plotted on a Cartesian coordinate system in twodimensions for a given valve size as depicted in FIG. 42. “Bendingcharacter” generally refers to the qualitative amount of wrinkles and/orcreases developed with in the leaflet structure during deformationsinduced by cyclic opening and closing. Conversely, as leaflet thicknessis decreased, the hydrodynamic performance behavior for a given geometryincreases while the bending character is reduced. This observation ofdifferences in bending character as a function of leaflet thickness isfurther illustrated with examples of two valves with 13 μm and 130 μmleaflet thicknesses, referred to as valve 42A and valve 42B,respectively. A graph of hydrodynamic performance data (EOA andregurgitant fraction) comparing these two valves is shown in FIG. 42where minimizing the regurgitant fraction and maximizing the EOA isdesirable.

It has been observed that thin film materials exposed to large cyclicdeformations over long durations are generally susceptible to wrinklesand creases. It is also generally known by those skilled in the art thatdurability of thin materials exposed to large cyclic deformations overlong durations is reduced as a result of such wrinkles and creases thatcan be formed during the duty cycle.

Therefore, it was surprising when leaflets of similar thickness (about16 μm) which were constructed from ultra thin composites (0.32 μm) andhad five times the number of layers (about 50) versus conventionalleaflets had the desirable bending behavior only previously achieved byleaflets having thicknesses of 75 μm or greater. Additionally, whencomparing durability of low number of layers of composites to highnumber of layers, the high number of layers typically out-perform thelow number of layers constructs by orders of magnitude using number ofduty cycles as a comparison. A valve with fifty layers and 16 μm thickleaflets was shown to have significantly fewer wrinkles and creases thana six layer construction of the approximately the same thickness.

Comparing leaflets of about the same thickness in cross section with 4,9, 26, 50, & 21 layers respectively, it was appreciated that theincrease in the number of layers facilitates both the ability of thelaminate to take a smaller bend radius as well as accommodate a tightcurvature by storing length of individual layers through localizedbuckling.

General trends that have been observed by varying the thickness andnumber of layers are illustrated in the graphs in FIGS. 41A and 41B andare further supported by the examples provided.

The following non-limiting examples are provided to further illustrateembodiments. It should also be readily appreciated that other valveframe designs may be used other than those illustrated in the examplesbelow and accompanying figures.

Example 1

Heart valve leaflets according to one embodiment were formed from acomposite material having an expanded fluoropolymer membrane and anelastomeric material and joined to a metallic balloon expandable stentusing an intermediate layer of FEP, as described by the followingprocess:

1) A thick, sacrificial tooling cushion pad or layer was formed byfolding a ePTFE layer over upon itself to create a total of four layers.The ePTFE layer was about 5 cm (2″) wide, about 0.5 mm (0.02″) thick andhad a high degree of compressibility, forming a cushion pad. Referringto FIGS. 1 and 2, the cushion pad 200 was then stretched (FIG. 2) onto aleaflet tool, generally indicated at 100. The leaflet tool 100 has aleaflet portion 102, a body portion 104 and a bottom end 106. Theleaflet portion 102 of the leaflet tool 100 has a generally arcuate,convex end surface 103. The cushion pad 200 was stretched and smoothedover the end surface 103 of the leaflet portion 102 of the leaflet tool100 by forcing the leaflet tool 100 in the direction depicted by thearrow (FIG. 2A). A peripheral edge 202 of the cushion pad 200 wasstretched over the bottom end 106 of the leaflet tool 100 and twisted tohold the cushion pad 200 in place (FIG. 2B).

2) Referring to FIG. 2B, a release layer 204 was then stretched over theleaflet portion 102 of the leaflet tool 100 which in the previous stepwas covered with the cushion pad 200. In one embodiment, the releaselayer 204 was made from a substantially nonporous ePTFE having a layerof fluorinated ethylene propylene (FEP) disposed along an outer surfaceor side thereof. The release layer 204 was stretched over the leaflettool 100 such that the FEP layer faced toward the cushion pad 200 andthe substantially nonporous ePTFE faced outwardly or away from thecushion pad 200. The release layer was about 25 μm thick and ofsufficient length and width to allow the release layer 204 to be pulledover the bottom end 106 of the leaflet tool 100. As with the cushion pad200 in the previous step, a peripheral edge 206 of the release layer 204was pulled toward the bottom end 106 of the leaflet tool 100 and thentwisted onto the bottom end 106 of the leaflet tool 100 to retain orhold the release layer 204 in place. The FEP layer of the release layer204 was then spot-melted and thereby fixedly secured to the cushion pad200, as required, by the use of a hot soldering iron.

3) The processes of Steps 1) and 2) were repeated to prepare threeseparate leaflet tools, each having a cushion pad covered by a releaselayer.

4) A leaflet material according to one embodiment was formed from acomposite material comprising a membrane of ePTFE imbibed with afluoroelastomer. A piece of the composite material approximately 10 cmwide was wrapped onto a circular mandrel to form a tube. The compositematerial was comprised of three layers: two outer layers of ePTFE and aninner layer of a fluoroelastomer disposed therebetween. The ePTFEmembrane was manufactured according to the general teachings describedin U.S. Pat. No. 7,306,729. The fluoroelastomer was formulated accordingto the general teachings described in U.S. Pat. No. 7,462,675.Additional fluoroelastomers may be suitable and are described in U.S.Publication No. 2004/0024448.

The ePTFE membrane had the following properties: thickness=about 15 μm;MTS in the highest strength direction=about 400 MPa; MTS strength in theorthogonal direction=about 250 MPa; Density=about 0.34 g/cm³; IBP=about660 KPa.

The copolymer consists essentially of between about 65 and 70 weightpercent perfluoromethyl vinyl ether and complementally about 35 and 30weight percent tetrafluoroethylene.

The percent weight of the fluoroelastomer relative to the ePTFE wasabout 53%.

The multi-layered composite had the following properties: thickness ofabout 40 μm; density of about 1.2 g/cm³; force to break/width in thehighest strength direction=about 0.953 kg/cm; tensile strength in thehighest strength direction=about 23.5 MPa (3,400 psi); force tobreak/width in the orthogonal direction=about 0.87 kg/cm; tensilestrength in the orthogonal direction=about 21.4 MPa (3100 psi), IPAbubble point greater than about 12.3 MPa, Gurley Number greater thanabout 1,800 seconds, and mass/area=about 14 g/m².

The following test methods were used to characterize the ePTFE layersand the multi-layered composite.

The thickness was measured with a Mutitoyo Snap Gage Absolute, 12.7 mm(0.50″) diameter foot, Model ID-C112E, Serial #10299, made in Japan. Thedensity was determined by a weight/volume calculation using anAnalytical Balance Mettler PM400 New Jersey, USA. The force to break andtensile strengths were measured using an Instron Model #5500R Norwood,Mass., load cell 50 kg, gage length=25.4 cm, crosshead speed=25mm/minute (strain rate=100% per minute) with flat faced jaws. The IPABubble Point was measured by an IPA bubble point tester, PressureRegulator Industrial Data Systems Model LG-APOK, Salt Lake City, Utah,USA, with a Ramp Rate of 1.38 KPa/s (0.2 psi/s), 3.14 cm² test area. TheGurley Number was determined as the time in seconds for 100 cm³ of airto flow through a 6.45 cm² sample at 124 mm of water pressure using aGurley Tester, Model #4110, Troy, N.Y., USA.

Unless otherwise noted, these test methods were used to generate thedata in subsequent examples.

Layers of the composite material, each having two outer layers of ePTFEand an inner layer of a fluoroelastomer disposed therebetween, waswrapped onto a mandrel having a diameter of about 28 mm (1.1″) such thatthe higher strength direction of the membrane was oriented in the axialdirection of the mandrel. In one embodiment, four layers of thecomposite material were wrapped in a non-helical, generallycircumferential fashion onto the mandrel. The composite material had aslight degree of tackiness that allowed the material to adhere toitself. While still on the mandrel, the composite material was slitlongitudinally generally along the mandrel long axis to form a sheetabout 10 cm (4″) by about 90 mm (3.5″).

5) The resulting sheet of leaflet material (or composite material fromStep 4) was then cut and wrapped onto the leaflet tool 100 having acushion pad 200 covered by a release layer 204. More specifically, asshown in FIGS. 3A-3C, the leaflet material 300 was placed onto a flatcutting surface. The leaflet tool 100 with the cushion pad 200 andrelease layer 204 was then aligned onto the leaflet material 300approximately as shown. Four slits 302, 304, 306, 308 were then formedin the leaflet material 300 with a razor blade. One pair of slits 302,304 extends from one side of the leaflet tool 100 and terminates at oneedge 300 a of the leaflet material 300, and the other pair of slits 306,308 extends from an opposite side of the leaflet tool 100 and terminatesat an opposite edge 300 b of the leaflet material 300. The slits 302,304, 306, 308 were spaced apart from the leaflet portion 102 of theleaflet tool 100. The slits 302, 304, 306, 308 did not protrude underthe leaflet tool 100. It should be appreciated that the widths of theindividual slits are shown not to scale. The slits 302, 304, 306, 308 inthe leaflet material 300 resulted in the formation of a folding portion310, a pair of straps 312, 314 and excess material of leaflet material315. The folding portions 310 were then folded in the general directionindicated by the arrows 316 in FIG. 3 and smoothed over the leaflet tool100, which was covered by the cushion pad 200 and the release layer 204in the previous steps.

6) The leaflet material 315 was then stretched and smoothed over theleaflet portion 102, particularly the end surface 103 of the leaflettool 100. The Steps 4) and 5) were repeated to form three separateleaflet assemblies. The three leaflet assemblies 402, 404, 406 were thenclamped together to form a tri-leaflet assembly 400, as shown in FIG. 4.Shown are the three separate leaflet assemblies 402, 404, 406, eachhaving an excess material of leaflet material 315 extending generallyradially beyond the periphery of the tri-leaflet assembly 400.

7) A base tool was then provided having cavities for engaging the endsurfaces of the leaflet tools of the tri-leaflet assembly and trimmingthe excess leaflet area to form three leaflets. Referring to FIG. 5A,the base tool is generally indicated at 500 and extends longitudinallybetween an end 501 and an opposite bottom end 503. Three concavecavities 502, 504, 506 are formed in the end 501 of the base tool 500.Each concave cavity 502, 504, 506 is formed to match fit or nestinglyseat the end surface 103 of one of the three leaflet assemblies 402,404, 406. Three radially extending elements 508, 510, 512 extendoutwardly from the end of the base tool 500. Each element 508, 510, 512is disposed between an adjacent pair of concave cavities 502, 504, 506.

The base tool 500 was then prepared having a compression pad and arelease layer (not shown) similar to how the leaflet tool was preparedin Steps 1 and 2. As described for each leaflet tool in Steps 1 and 2,the compression pad and the release layer were similarly stretched andaffixed to the base tool 500 to form a base tool assembly.

8) Referring to FIG. 5B, the base tool assembly (illustrated forconvenience as the base tool 500 without showing the cushion pad and therelease layer) and the tri-leaflet assembly, generally indicated at 400,were then generally axially aligned together so that the end surface(not shown) of each leaflet tool 100 was seated into one of the concavecavities (not shown) in the end 501 of the base tool, generallyindicated at 500, to form a combined tool assembly.

9) A metallic balloon expandable stent was then fabricated. A tube of316 stainless steel having a wall thickness of about 0.5 mm (0.020″) anda diameter of about 2.5 cm (1.0″) was laser cut. A pattern was cut intothe tube to form an annular-shaped cut stent frame or support structure,which is generally indicated at 600 and shown illustratively in a flat,plane view in FIG. 6 a. The support structure 600, includes a pluralityof small closed cells 602, a plurality of large closed cells 604, and aplurality of leaflet closed cells 606. Note that one of the plurality ofleaflet closed cells 606 appears as an open cell in FIG. 6A due to theflat plane view. The cells 602, 604, 606 are generally arranged alongrows forming the annular shape of the support structure 600.

10) Polymeric materials were then adhered to the laser cut stent frame.First, a sacrificial compression layer of ePTFE membrane was wrappedwithout overlap onto a mandrel (not shown) having a diameter of about2.5 cm (1.0″). The sacrificial compression layer of ePTFE membrane had athickness of about 0.5 mm (0.02″) and a width of about 10 cm (4″), andwas compliant and compressible to provide a soft, sacrificialcompression layer.

11) Four layers of a substantially nonporous, ePTFE film were thenwrapped onto the mandrel on top of the compression layer membrane. Thesubstantially nonporous, ePTFE film had a thickness of about 25 μm(0.001″), was about 10 cm (4″) wide and had a layer of FEP on one side.The substantially nonporous, ePTFE film was wrapped with the FEP facingaway from the mandrel. The substantially nonporous, ePTFE film had theproperties of the release layer previously described in Step 2).

12) A thin film of type 1 (ASTM D3368) FEP was constructed using meltextrusion and stretching. An additional 10 layers of this type 1 (ASTMD3368) FEP film was added to the mandrel, which was previously wrappedin the compression layer membrane in Step 10 and the four layers ofsubstantially nonporous, ePTFE film in Step 11. The type 1 (ASTM D3368)FEP film was about 40 μm (0.0016″) thick and was about 7.7 cm (3″) wide.

13) The wrapped mandrel was then heat treated in an air convection ovenat about 320° C. for about 5 minutes and allowed to cool.

14) The support structure (indicated at 600 in FIG. 6A) was then placedonto the heat treated and wrapped mandrel. Two additional layers of type1 (ASTM D3368) FEP film (provided in Step 12) were then wrapped onto thesupport structure, which was previously placed on the wrapped mandrel.

15) The wrapped mandrel and the support structure supported thereon werethen heat treated in an air convection oven at about 320° C. for about10 minutes and allowed to cool, forming a polymeric-coated supportstructure.

16) The polymeric-coated support structure was then trimmed with ascalpel to form a trimmed stent frame, which is generally indicated at700 and shown illustratively in a flat, plane view in FIG. 6B. Morespecifically, in one manner, the polymeric coating was trimmed about 2mm (0.08″) past the edges of the support structure (600, FIG. 6A) toform a variety of edge profiles 708. In another manner, the polymericcoating was allowed to span entire cells to form a web in each cell. Ineither case, the support structure 600 was fully encapsulated within apolymeric coating 702 to form the trimmed stent frame 700. The trimmedstent frame 700 includes a plurality of leaflet openings 704corresponding in number and generally in shape to the plurality ofleaflet closed cells 606 (FIG. 6A). Further, a slit 706 is formed in thepolymeric coating 702 of each of the small closed cells as shown in FIG.6B. Specifically, each slit 706 is linear and generally parallel to alongitudinal center axis (not shown) of the annular-shaped supportstructure 600.

17) The trimmed stent frame was then placed onto the combined toolassembly from Step 8. The leaflet portions (102) of the leaflet toolswere aligned to the leaflet openings (704 in FIG. 6B) in the trimmedstent frame. The three excess leaflet material areas (315 in FIG. 4)were pulled through the leaflet openings of the stent frame. Each of thethree pairs of straps (312, 314 in FIG. 3A) was pulled through one ofthe slits (706 in FIG. 6B) and wrapped around the trimmed stent frame.Each pair of straps were wrapped in opposing directions relative to eachother. The six straps were then heat tacked to the trimmed stent frameusing a hot soldering iron.

18) The combined tool assembly (Step 8) and the trimmed stent framehaving the wrapped and heat tacked straps were then mounted into arotary chuck mechanism. The rotary chuck mechanism was then adjusted toapply a light, longitudinal compressive load. The excess leafletmaterial areas (315 in FIG. 4) were then heat tacked to the base tool(500 in FIG. 5) using a hot soldering iron.

19) The combined tools of Step 18 were then wrapped with an additional 2layers of type 1 (ASTM D3368) FEP film (from Step 12). Three additionallayers of the composite (Step 4) were then overwrapped and tacked downto the trimmed stent frame.

20) In preparation for a final heat treat, release and sacrificiallayers of a compression tape and compression fiber were applied bothcircumferentially and longitudinally to the assembly from Step 19. Thecompression tape/fiber contact and compress the assembly bothcircumferentially and longitudinally during the subsequent heat treat. Asacrificial layer of compression tape was circumferentially wrapped in ahelical fashion onto the assembly from Step 19. This compression tapehad the properties of the sacrificial compression layer of ePTFEpreviously described in Step 10. An ePTFE compression fiber was thentightly wrapped onto the compression tape. Approximately 100 turns ofthe compression fiber were circumferentially applied in a closely spacedhelical pattern. The ePTFE compression fiber was about 1 mm (0.04″) indiameter and was structured to shrink longitudinally when sufficientlyheated. The clamped assembly was then removed from the rotary chuckmechanism. Three layers of sacrificial compression tape were thenwrapped in a longitudinal fashion around the assembly. Approximately 20wraps of the compression fiber was then longitudinally wrapped over thelongitudinal compression tape.

21) The assembly from Step 20 was then heat treated in an air convectionoven at about 280° C. for about 90 minutes and then room temperaturewater quenched. This heat treatment step facilitates the flow of thethermoplastic fluoroelastomer into the pores of the ePTFE membrane usedto create the leaflet material described in step 4.

22) The sacrificial compression tapes/fibers were then removed. Thepolymeric materials were trimmed to allow the leaflet and base tools tobe separated. The stent polymeric layers were then trimmed to allowremoval of the stent frame with the attached leaflets. The leaflets werethen trimmed, resulting in a valve assembly as shown in FIG. 8 andgenerally indicated at 800.

The resulting valve assembly 800, according to one embodiment, includesleaflets 802 formed from a composite material with at least onefluoropolymer layer having a plurality of pores and an elastomer presentin substantially all of the pores of the at least one fluoropolymerlayer. Each leaflet 802 is movable between a closed position, shownillustratively in FIG. 9A, in which blood is prevented from flowingthrough the valve assembly, and an open position, shown illustrativelyin FIG. 9B, in which blood is allowed to flow through the valveassembly. Thus, the leaflets 802 of the valve assembly 800 cycle betweenthe closed and open positions generally to regulate blood flow directionin a human patient,

The performance of the valve leaflets in each valve assembly wascharacterized on a real-time pulse duplicator that measured typicalanatomical pressures and flows across the valve, generating an initialor “zero fatigue” set of data for that particular valve assembly. Thevalve assembly was then transferred to a high-rate fatigue tester andwas subjected to approximately 207 million cycles. After each block ofabout 100 million cycles, the valve was then returned to the real-timepulse duplicator and the performance parameters re-measured.

The flow performance was characterized by the following process:

1) The valve assembly was potted into a silicone annular ring (supportstructure) to allow the valve assembly to be subsequently evaluated in areal-time pulse duplicator. The potting process was performed accordingto the recommendations of the pulse duplicator manufacturer (ViVitroLaboratories Inc., Victoria BC, Canada)

2) The potted valve assembly was then placed into a real-time left heartflow pulse duplicator system. The flow pulse duplicator system includedthe following components supplied by VSI Vivitro Systems Inc., VictoriaBC, Canada: a Super Pump, Servo Power Amplifier Part Number SPA 3891; aSuper Pump Head, Part Number SPH 5891B, 38.320 cm² cylinder area; avalve station/fixture; a Wave Form Generator, TriPack Part Number TP2001; a Sensor Interface, Part Number VB 2004; a Sensor AmplifierComponent, Part Number AM 9991; and a Square Wave Electro Magnetic FlowMeter, Carolina Medical Electronics Inc., East Bend, N.C., USA.

In general, the flow pulse duplicator system uses a fixed displacement,piston pump to produce a desired fluid flow through the valve undertest.

3) The heart flow pulse duplicator system was adjusted to produce thedesired flow, mean pressure, and simulated pulse rate. The valve undertest was then cycled for about 5 to 20 minutes.

4) Pressure and flow data were measured and collected during the testperiod, including ventricular pressures, aortic pressures, flow rates,and pump piston position. Shown illustratively in FIG. 10 is a graph oftypical data outputs from the heart flow pulse duplicator system.

5) Parameters used to characterize the valve and to compare topost-fatigue values are pressure drop across the open valve during thepositive pressure portion of forward flow, effective orifice area, andregurgitant fraction.

Following characterization, the valve assembly was then removed from theflow pulse duplicator system and placed into a high-rate fatigue tester.A Six Position Heart Valve Durability Tester, Part Number M6 wassupplied by Dynatek, Galena, Mo., USA and was driven by a Dynatek DaltaDC 7000 Controller. This high rate fatigue tester displaces fluidthrough a valve assembly with a typical cycle rate of about 780 cyclesper minute. During the test, the valve assembly can be visually examinedusing a tuned strobe light. The pressure drop across the closed valvecan also be monitored as displayed in FIGS. 11A and 11B. Shown in FIGS.11A and 11B is a typical data set verifying that the high-rate fatiguetester was producing consistent pressure wave forms.

The valve assembly was continuously cycled and periodically monitoredfor visual and pressure drop changes. After approximately 200 millioncycles, the valve assembly was removed from the high-rate tester andreturned to the real-time pulse duplicator. The pressure and flow datawere collected and compared to the original data collected.

Shown in FIG. 12A is a screen shot displaying typical measured dataoutputs from the real-time heart flow pulse duplicator system. Shown areVentricular Pressures, Aortic Pressures and Flow Rate. The initial orzero fatigue data for a particular valve is shown illustratively in FIG.12A. The same measurements were taken and data were collected for thesame particular valve after 207 million cycles. The 207 million cycledata for the particular valve is shown illustratively in FIG. 12B. Bothsets of measurements were taken at 5 liters per minute flow rate and 70cycles per minute rate. Comparing FIGS. 12A and 12B, it should bereadily appreciated that the waveforms are substantially similar,indicating no substantial change in the valve leaflet performance afterabout 207 million cycles. Pressure drop, effective orifice area (EOA),and regurgitant fraction measured at zero and 207 million cycles aresummarized in Table 1 below.

TABLE 1 Number of Pressure Regurgitant cycles Drop EOA Fraction(Million) (mmHg) (cm²) (%) 0 5.7 2.78 12.7 207 7.7 2.38 9.6

Generally, it was observed that the valve leaflets constructed accordingto the embodiments described herein exhibited no physical or mechanicaldegradation, such as tears, holes, permanent set and the like, after 207million cycles. As a result, there was also no observable change ordegradation in the closed and open configurations of the valve leafletseven after 207 million cycles.

Example 2

A heart valve having polymeric leaflets joined to a rigid metallic framewas constructed according to the following process:

A mandrel 900 was machined from PTFE having a shape shown in FIG. 14.The mandrel 900 has a first end 902 and an opposite second end 904, andextends longitudinally therebetween. The mandrel 900 has an outersurface 910 having three (two shown) generally arcuate, convex lobes912, each generally for forming leaflets (not shown) of a finished valveassembly (not shown). The outer surface 910 also includes a frameseating area 920 for positioning a valve frame (930 in FIG. 15) relativeto the convex lobes 912 prior to formation of leaflets onto the valveframe.

As shown in FIG. 15, a valve frame 930 was laser cut from a length of316 stainless steel tube with an outside diameter of about 25.4 mm and awall thickness of about 0.5 mm in the shape shown in FIG. 15. In theembodiment shown, the valve frame 930 extends axially between a bottomend 932 and an opposite top end defined generally by a plurality ofaxially extending, generally spire shaped posts 934 corresponding to thenumber of leaflets in the intended finished valve assembly (not shown).In the specific embodiment shown, three posts 934 are formed in thevalve frame 930.

Two layers of an about 4 μm thick film of FEP (not shown) was wrappedaround the valve frame 930 and baked in an oven for about 30 minutes atabout 270° C. and allowed to cool. The resulting covered valve frame(for clarity, shown uncovered and indicated at 930) was then slid ontothe mandrel 900 so that the complementary features between the valveframe 930 and mandrel 900 are nested together, as shown in FIG. 16.

A leaflet material was then prepared having a membrane of ePTFE imbibedwith a fluoroelastomer. More specifically, the membrane of ePTFE wasmanufactured according to the general teachings described in U.S. Pat.No. 7,306,729. The ePTFE membrane was tested in accordance with themethods described in the Appendix. The ePTFE membrane had a mass perarea of about 0.57 g/m², a porosity of about 90.4%, a thickness of about2.5 μm, a bubble point of about 458 KPa, a matrix tensile strength ofabout 339 MPa in the longitudinal direction and about 257 MPa in thetransverse direction. This membrane was imbibed with the samefluoroelastomer as described in Example 1. The fluoroelastomer wasdissolved in Novec HFE7500, 3M, St Paul, Minn., USA in an about 2.5%concentration. The solution was coated using a mayer bar onto the ePTFEmembrane (while being supported by a polypropylene release film) anddried in a convection oven set to about 145° C. for about 30 seconds.After two coating steps, the resulting composite material ofePTFE/fluoroelastomer had a mass per area of about 3.6 g/m².

The composite material (not shown) was then wound around the assembledmandrel 900 and valve frame 930. In one embodiment, a total of 20 layersof the ePTFE/fluoroelastomer composite was used. Any excess compositematerial that extended beyond the ends of mandrel 900 were twisted andpressed lightly against the ends 902, 904 of the mandrel 900.

The composite material wrapped mandrel was then mounted in a pressurevessel so that a vent port 906 (FIG. 14) in the base or second end 904of the mandrel 900 was plumbed to atmosphere. The vent port 906 extendsfrom the second end 904 axially through the mandrel 900 and communicatesto a generally orthogonally extending vent port 908 that extends throughthe outer surface 910 of the mandrel 900. The vent ports 906, 908, inaddition to other vent ports which may be provided in the mandrel asneeded (not shown), allow trapped air between the composite material andthe mandrel to escape during the molding process.

About 690 KPa (100 psi) of nitrogen pressure was applied to the pressurevessel, forcing the ePTFE/fluoroelastomer composite against the mandrel900 and the valve frame 930. Heat was applied to the pressure vesseluntil the temperature inside the vessel reached about 300° C., about 3hours later. The heater was turned off and the pressure vessel wasallowed to cool to room temperature overnight. This process thermallybonded the layers of ePTFE/fluoroelastomer composite to each other andto the FEP coating on the valve frame 930. The pressure was released andthe mandrel was removed from the pressure vessel.

The ePTFE/fluoroelastomer composite was trimmed circumferentially in twoplaces: first, at the bottom end 932 of the valve frame 930, and second,near the top end of the valve frame 930 along a circle generallyintersecting near the mid-point of each post 934. The resulting valveassembly 940 consisting of the valve frame 930 and the trimmed compositematerial was separated from and slid off the mandrel The molded valveassembly 940, as shown in FIG. 17, includes the valve frame 930 and aplurality of leaflets 950 formed from the trimmed composite material. Inone embodiment, the valve assembly 940 included three leaflets. Inanother embodiment, each leaflet 950 in the valve assembly 940 wasapproximately 40 μm thick.

To help control the degree of opening of the valve, adjacent leafletsabout each post were bonded together. As shown in FIG. 18, the adjacentleaflets 950 a, 950 b were wrapped around the post 934 and bondedtogether to form a seam 954. The seam 954 had a depth 956 extending toat least about 2 mm from the post 934. To support the bond between theadjacent leaflets 950 a, 950 b, an attachment member 952 was fixedlysecured to inner surfaces of the adjacent leaflets 950 a, 950 b therebybridging the seam 954 between the adjacent leaflets 950 a, 950 b. Asshown in FIG. 18, the attachment member 952 was generally rectangular.It should be appreciated, however, that other shapes for the attachmentmember may be utilized. The attachment member 952 was formed from thesame type of composite material used to form the leaflets 950. Theattachment member 952 was fixedly secured to the inner surfaces of theadjacent leaflets 950 a, 950 b using the fluoroelastomer solutionpreviously described. These steps were repeated for the other pairs ofadjacent leaflets of the valve assembly.

The performance and durability of the valve leaflets in this examplewere analyzed in the same manner as described in Example 1. The valveassembly was initially characterized on the same real-time pulseduplicator as described in Example 1 that measured typical anatomicalpressures and flows across the valve, generating an initial or “zerofatigue” set of data for that particular valve assembly. The valve wasthen subjected to accelerated testing as in Example 1. After about 79million cycles, the valve was removed from the high rate fatigue testerand the hydrodynamic performance again characterized as in Example 1.The valve was removed finally at about 198 million cycles. Pressuredrop, EOA and regurgitant fraction measured at about 79 million cyclesand about 198 cycles are summarized in Table 2 below.

FIGS. 13A and 13B display similar results for a similar valve. FIG. 13Ais a graph of measured data output from the heart flow pulse duplicatorsystem taken after about 79 million cycles. The same measurements weretaken for the similar valve after about 198 million cycles, a graph ofwhich is shown illustratively in FIG. 13B. Both sets of measurementswere taken at about 4 liters per minute flow rate and about 70 cyclesper minute rate. Comparing FIGS. 13A and 13B, it should be againappreciated that the waveforms are significantly similar, indicating nosubstantial change in the valve leaflet performance after about 198million cycles. Pressure drop, effective orifice area (EOA), andregurgitant fraction measured at 0, about 79, and about 198 millioncycles are summarized in Table 2 below. These data indicate nosubstantial change in the valve leaflet performance after about 198million cycles.

TABLE 2 Number of Pressure Regurgitant Cycles Drop EOA Fraction(Million) (mmHg) (cm²) (%) 0 6.8 2.56 7.8 79 5.4 2.58 10.25 198 4.4 2.6010.1

Example 3

A heart valve having polymeric leaflets joined to a rigid metallic framewas constructed according to the following process:

A valve support structure or frame 960 was laser cut from a length of316 stainless steel tube with an outside diameter of about 25.4 mm and awall thickness of about 0.5 mm in the shape shown in FIG. 19. In theembodiment shown, the frame 960 extends axially between a bottom end 962and an opposite top end defined generally by a plurality of axiallyextending, generally spire shaped posts 964 corresponding to the numberof leaflets in the intended finished valve assembly (not shown). Aparabolically shaped top edge 968 extends between adjacent posts 964.The parabolically shaped top edge 968 and posts 964 define a leafletsupport frame. In the specific embodiment shown, three posts 964 andthree top edges 968 form the top end of the frame 960. The corners ofthe frame that would be in contact with the leaflet material wererounded using a rotary sander and hand polished. The frame was rinsedwith water and then plasma cleaned using a PT2000P plasma treatmentsystem, Tri-Star Technologies, El Segundo, Calif., USA.

In one embodiment, a cushion member is provided between at least aportion of the frame and at least a portion of the leaflet to minimizestress related to direct contact between the frame and the leaflet. Acomposite fiber of ePTFE and silicone was created by first imbibing anePTFE membrane with silicone MED-6215 (NuSil, Carpinteria, Calif., USA),slitting it to a width of about 25 mm, and rolling into a substantiallyround fiber. The ePTFE used in this fiber was tested in accordance withthe methods described in the Appendix. The ePTFE membrane had a bubblepoint of about 217 KPa, a thickness of about 10 μm, a mass per area ofabout 5.2 g/m², a porosity of about 78%, a matrix tensile strength inone direction of about 96 MPa, and a matrix tensile strength of about 55MPa in an orthogonal direction. The composite fiber 966 was wrappedaround each of the posts 964 of the frame 960 as shown in FIG. 20.

A mandrel 970 was formed using stereolithography in a shape shown inFIG. 21. The mandrel 970 has a first end 972 and an opposite second end974, and extends longitudinally therebetween. The mandrel 970 has anouter surface 980 having three (two shown) generally arcuate, convexlobes 982, each generally for forming leaflets (not shown) of a finishedvalve assembly (not shown). The outer surface 980 also includes a frameseating area 984 for positioning the frame (960 in FIG. 19) relative tothe convex lobes 982 prior to formation of the valve leaflets onto thevalve frame.

The mandrel 970 was then spray coated with a PTFE mold release agent.Four layers of the ePTFE membrane previously described in this examplewere wrapped around the mandrel to form an inner composite layer.MED-6215 was wiped onto the ePTFE and allowed to wet into andsubstantially fill the pores of the ePTFE. Excess MED-6215 was blottedoff and the frame 960 with the composite fiber 966 wrapped posts 964 waspositioned on the mandrel 970 along the frame seating area 984, as shownin FIG. 22. Silicone MED-4720, NuSil, Carpinteria, Calif., USA wasplaced along the top edges 968 of the frame 960 and along the posts 964of the frame 960 to create a strain relief within the leaflet (notshown). Eight additional layers of ePTFE were wrapped around the frame960 and mandrel 970. Additional MED-6215 was wiped onto the ePTFE andallowed to wet into and substantially fill the pores of the ePTFE.Another 8 layers of ePTFE were wrapped around the frame 960 and mandrel970 to form an outer composite layer. These layers form a blotter toabsorb any excess silicone during the molding process and were removedafter the silicone had cured. The frame 960 was therefore sandwichedbetween the inner composite layer and outer composite layer on theinside and outside surface of the frame 960, respectively, and theleaflets 992 being coupled to and supported by the leaflet supportframe. The leaflets 992 being comprised of the inner composite layer andouter composite layer coupled together.

Silicone rubber forms (not shown) molded with one surface exactlymatching the inverse shape of the mandrel surface were previouslyfabricated for each of the 3 leaflet-forming features. These forms werespray coated with PTFE mold release and then mated to the matchingfeature of the mandrel. Approximately 50 wraps of an ePTFE fiber (notshown) were wound around the silicone forms to apply generally radialpressure to the valve against the mandrel.

This assembly was then placed in an oven at about 100° C. for about 1hour to cure the silicone. After cooling, the fiber and silicone formswere removed, the 8 layers of blotter ePTFE were peeled away anddiscarded, and the resulting valve (not shown) was slid off of themandrel. The posts were trimmed using wire cutters and the excess lengthof leaflet material and excess length of material at the base of theframe was carefully trimmed using scissors to form a completed valveassembly, which is shown and generally indicated at 990 in FIG. 23.Thus, in one embodiment, the valve assembly 990 was formed having theframe or support structure 960; a plurality of leaflets 992 supported onthe support structure 960 and movable between open and closed positionsto regulate blood flow through the valve assembly 990; and a compositefiber 966 wrapped post 964 located between at least a portion of thesupport structure 960 and at least a portion of each leaflet 992 tominimize stress in the leaflets due to the coupling and/or proximity ofthe leaflets to the support structure. In another embodiment, thecushion member is formed from a composite material with at least onefluoropolymer layer having a plurality of pores and an elastomer presentin substantially all of the pores, as described above. The periphery ofthe leaflet 992, except for the free edge, is supported by the leafletsupport frame defined by the parabolically shaped top edge 968 and posts964. The leaflet defines a free edge not coupled to the supportstructure, each leaflet being movable between open and closed positions.

It should be appreciated that support structures other than asspecifically shown in the figures may be utilized. Further, cushionmembers may be utilized anywhere along the support structure asnecessary to minimize stress in the leaflets due to the coupling and/orproximity of the leaflets to the support structure. For example, cushionmember(s) may be coupled to the support structure along theparabolically shaped top edge.

It should also be appreciated that the cushion members may be formed assheets and wrapped around desired locations along the support structure,or be formed from fibers of various cross sectional shapes and sizes.

It should also be appreciated that the cushion members may be formed astubes and slid over the ends of the support structure, or be slitlongitudinally and positioned around the desired location along thesupport structure.

The leaflets of the complete valve assembly were measured and determinedto have an average thickness at the center of each leaflet of about 120μm.

The valve assembly was then characterized for flow performance andsubjected to accelerated testing as in Example 1. After each block ofabout 50 million cycles, the valve assembly was removed from the highrate fatigue tester and the hydrodynamic performance again characterizedas in Example 1. The valve assembly was removed finally at about 150million cycles and demonstrated acceptable performance and no holeformation.

Comparative Example A

Six valves were constructed in the manner of Example 1 with theexception that the elastomer was not incorporated. The ePTFE materialwas the same as that described in Example 1, but it was not imbibed withthe fluoroelastomer copolymer and was instead coated with adiscontinuous layer of FEP copolymer that served as a thermoplasticadhesive. Valves were constructed as in Example 1 with each leafletcomprising 3 layers of membrane resulting in a final leaflet thicknessaveraging about 20 μm. After hydrodynamic characterization, the valveswere mounted in the Dynatek accelerated tester described in Example 1.By about 40 million cycles, edge delamination and hole formation in theleaflets was observed and the test was stopped.

Comparative Example B

Two valves were constructed in the manner of Example 1 but did notincorporate the elastomer portion of the embodiments. The materialemployed was thin ePTFE membrane possessing properties similar to thefollowing: a mass per area of about 2.43 g/m², a porosity of about 88%,an IBP of about 4.8 KPa, a thickness of about 13.8 μm, a matrix tensilestrength in one direction of about 662 MPa, and a matrix tensilestrength of about 1.2 MPa in the orthogonal direction. The ePTFEmembrane was tested in accordance with the methods described in theAppendix. Ten layers of the membrane were placed in alternatingdirections onto a stack and then placed on the tooling as described inExample 1. The tooling was then exposed to about 350° C. in a convectionair oven for about 25 minutes, removed and quenched in a water bath. Thethree pieces of tooling were then inserted into the stent frame and theleaflets bonded to the valve assembly with FEP as in Example 1.

Each valve was subjected to high-rate fatigue testing using thereal-time heart flow pulse duplicator system, as described above. Afterabout 30 million cycles on one valve and about 40 million cycles onanother valve, visual degradation, including stiffening and deformation,was observed and measurable decrease in performance was noted. Inaddition to the visual and measurable degradation in performance, Table3 below summarizes the pressure drop, effective orifice area (EOA), andregurgitant fraction measured after about 40 million cycles.

TABLE 3 Number of Pressure Cycles Drop EOA Regurgitant (Millions) (mmHg)(cm²) Fraction (%) 0 3.9 3.11 8.1 40 × 10⁶ 6.5 2.85 14.1

The material properties of the following non-limiting examples areprovided in FIG. 43, Table 4, for reference to the individualdescriptions, wherein like parts from the previous exemplary embodimentsare enumerated with like prime numerals.

Example 4a

In exemplary embodiments, a heart valve having polymeric leaflets formedfrom a composite material having an expanded fluoropolymer membrane andan elastomeric material and joined to a semi-rigid, non-collapsiblemetallic frame, and further a having strain relief and sewing ring wasconstructed according to the following process:

A valve frame was laser machined from a length of MP35N cobalt chromiumtube hard tempered with an outside diameter of 26.0 mm and a wallthickness of 0.6 mm in the shape shown illustratively and generallyindicated at 1000 in FIG. 24. The frame 1000 was electro-polishedresulting in 0.0127 mm material removal from each surface and leavingthe edges rounded. The frame 1000 was exposed to a surface rougheningstep to improve adherence of leaflets to the frame 1000, withoutdegrading fatigue durability performance. The frame 1000 was cleaned bysubmersion in an ultrasonic bath of acetone for approximately fiveminutes. The entire metal frame surface was then subjected to a plasmatreatment using methods commonly known to those having ordinary skill inthe art. This treatment also served to improve the wetting of thefluorinated ethylene propylene (FEP) adhesive.

FEP powder (Daikin America, Orangeburg N.Y.) was then applied to theframe. More specifically, the FEP powder was stirred to form an airborne“cloud” in an enclosed blending apparatus, such as a standard kitchentype blender, while the frame is suspended in the cloud. The frame wasexposed to the FEP powder cloud until a uniform layer of powder wasadhered to the entire surface of the frame. The frame was then subjectedto a thermal treatment by placing it in a forced air oven set to 320° C.for approximately three minutes. This caused the powder to melt andadhere as a thin coating over the entire frame. The frame was removedfrom the oven and left to cool to room temperature.

The strain relief and sewing ring were attached to the frame in thefollowing manner. A 23 mm diameter cylindrical mandrel was wrapped witha single layer of Kapton® (El DuPont de Nemours, Inc., Wilmigton, Del.)polyimide film and held in place by an adhesive strip of Kapton® tapeover the length of the overlapping seam. One wrap of a two layerlaminate consisting of an ePTFE membrane laminated to a 25.4 μm thicklayer of fluoroelastomer, as described in Example 1, was wrapped withthe high strength of the membrane aligned along a direction generallyparallel with the axis of the Kapton®-covered mandrel with nosubstantially overlap at the seam. The frame was aligned coaxially overthe wrapped mandrel. An additional wrap of the two layer laminate waswrapped onto the mandrel encapsulating the entire frame with the seamoriented 180° from the seam of the single inner wrap. The four layerlaminate was end cut about 135 mm from the base of the frameencapsulated within. The four layer laminate was hand rolled axially inthe toward the base of the frame until the 135 mm length of materialformed an approximate 3 mm outer diameter ring adjacent to the base ofthe frame. The four layer laminate was end cut approximately 20 mm fromthe top of the frame and the assembly was compression wrapped helicallywith two sacrificial layers of ePTFE membrane imbibed with a polyimide,four layers of unsintered ePTFE membrane, and approximately one hundredwraps of an ePTFE fiber. The entire assembly was subjected to a thermaltreatment by placing it in a forced air oven set to 280° C. for fiveminutes and returned to room temperature by immediate water quench uponremoval from the oven. The sacrificial layers were removed and the fourlayer laminate at the top end of the frame trimmed to allow about a 2 mmlength to extend beyond the perimeter of the top of the frame. Themandrel and Kapton were then removed from the interior of the frameresulting in the frame assembly, generally indicated at 1010 in FIG. 25,having the strain relief 1012 and sewing ring 1014 with the frame 1000laminated within.

A single female mold or base tool, shown illustratively and indicated at50 in FIG. 5 a, is provided with concave cavities (502, 504, 506)generally defining the shape of the tri-leaflet. Three male molds orleaflet tools (100) are provided with end surfaces (103) correspondingin shape and contour with the concave cavities in the base tool. Theleaflet tools are pivotally coupled to each other, which helps tomaintain relative axial and rotational spacing as depicted in thetri-leaflet assembly (400) in FIG. 5 a. The base and leaflet tools arewrapped with a single layer of un-sintered ePTFE membrane to form acushioning layer and then a single layer of substantially nonporousePTFE membrane with FEP on one side is used to adhere the membranestogether and onto the mandrels with a soldering iron. The sacrificiallayers ensure that all the mating surfaces between the base and leaflettools have a cushioning layer when compressed together; an additionalfunction is as a release layer to prevent the leaflet material fromadhering to the tools. The base and leaflet tools are initially combinedto create a single cylindrical structure or combined tool assembly, asdepicted in FIG. 5 b, to facilitate leaflet construction and attachmentto the frame with the strain relief and sewing ring component via a tapewrapping process, as discussed in detail below.

A leaflet material was then prepared. A membrane of ePTFE wasmanufactured according to the general teachings described in U.S. Pat.No. 7,306,729. The ePTFE membrane had a mass per area of 1.15 g/m², abubble point of 79.7 MPa, a thickness of about 1016 nm, a matrix tensilestrength of 410.9 MPa in the longitudinal direction and 315.4 MPa in thetransverse direction. This membrane was imbibed with a fluoroelastomer,as described above in Example 1. The fluoroelastomer was dissolved inNovec HFE7500 (3M, St Paul, Minn.) in a 2.5% concentration. The solutionwas coated using a mayer bar onto the ePTFE membrane (while beingsupported by a polypropylene release film) and dried in a convectionoven set to 145° C. for 30 seconds. After 2 coating steps, the finalePTFE/fluoroelastomer or composite had a mass per area of 4.08 g/m²,28.22% fluoropolymer by weight, a dome burst strength of 15.9 KPa, andthickness of 1.93 μm.

Three layers of the leaflet or composite material was wrapped around thecombined tool assembly with an elastomer rich side of the compositefacing away from the tools. In exemplary embodiments, the compositematerial is oriented to have a predetermined matrix tensile strengthalong a direction generally parallel with the longitudinal axis of thecombined tool assembly. More specifically, the predetermined matrixtensile strength is about 410 MPa.

Referring to FIGS. 26 a and 26 b, the frame assembly 1010 was positionedco-axially onto the combined tool assembly, generally indicated at 1020,over the three inner wraps of the composite material. The frame assembly1010 was also aligned rotationally to match the features of the basetool 500′, as depicted in FIG. 26 a. Twenty-three additional layers ofthe composite material were wrapped around the combined tool assembly1020 with the elastomer rich side of each layer facing toward the toolspreviously wrapped by the three aforementioned layers of compositematerial. In exemplary embodiments, the additional layers of thecomposite material were each oriented to have a predetermined matrixtensile strength along a direction generally parallel with thelongitudinal axis of the combined tool assembly. In one embodiment, thepredetermined matrix tensile strength was about 410 MPa. The leaflettools 100′ were then removed from underneath the twenty-six layercomposite laminate tube.

Each of the leaflet tools 100′ was then moved rotatably about itsrespective end pivot, as depicted in FIG. 26 b, to allow the compositelaminate tube 1015 from the previous step to be positioned between theleaflet tools 100′. The leaflet tool assembly was coaxially aligned tothe base tool 500′ and the leaflet tools 100′ rotated inwardly towardeach other to compress the twenty-six layer composite laminate tube ontothe female tri-leaflet mold surface configuration of the base tool 500′.The combined tool assembly comprising the leaflet and base tools,composite laminate, strain relief, frame, and sewing ring was thenmounted between fixed and translational portions of a fixture. Bothradial and axial compression were applied by radially clamping theleaflet tools 100′ while simultaneously applying an axial load with thetranslational end of the fixture.

The combined tool assembly was then compression wrapped helically withtwo sacrificial layers of compliant ePTFE membrane imbibed with apolyimide, four layers of un-sintered ePTFE membrane, and approximatelyone hundred wraps of an ePTFE fiber. The entire assembly was removedfrom the lathe and placed in a clamping fixture to maintain axialcompression while subjected to a thermal treatment by placing it in aforced air oven set to about 280° C. for about 30 minutes. The assemblywas removed from the oven and brought back to room temperature viaimmediate water quench. The sacrificial layers, leaflet and base toolswere removed leaving a fully adhered valve in a closed three dimensionalform.

The excess leaflet material was trimmed with scissors from the top ofthe frame posts to the common triple point of each leaflet to createthree commissures or coapting surface regions as depicted in FIG. 27.The leaflets were opened with an ePTFE mandrel tapered from 10 mm to 25mm. The annular sewing ring 1014 at the base of the frame 1000 wasmolded into a flange by placing the frame assembly 1010 betweencorresponding halves 1030 a, 1030 b of a fixture, as illustrated inFIGS. 28 and 29 and placing the assembly in an ultrasonic compressionwelder (not shown), such as a model #8400 ultrasonic compression weldermade by Branson ultrasonics, Danbury Conn. A weld time of about 0.8seconds, hold time of about 3.0 seconds, and pneumatic pressure of about0.35 MPa was applied to the assembly. The ultrasonic welding process wasperformed twice to create a sewing ring flange thickness ofapproximately 2 mm with an outer diameter of 33 mm. The final valveassembly is shown illustratively and generally indicated at 1100 in FIG.30.

The final leaflet was comprised of 28.22% fluoropolymer by weight with athickness of 50.3 μm. Each leaflet had 26 layers of the composite and aratio of thickness/number of layers of 1.93 μm.

The resulting valve assembly 1100 includes leaflets 1102 formed from acomposite material with more than one fluoropolymer layer having aplurality of pores and an elastomer present in substantially all of thepores of the more than one fluoropolymer layer. Each leaflet 1102 ismovable between a closed position, shown illustratively in FIG. 30A, inwhich blood is substantially prevented from flowing through the valveassembly, and an open position, shown illustratively in FIG. 30B, inwhich blood is allowed to flow through the valve assembly. Thus, theleaflets 1102 of the valve assembly 1100 cycle between the closed andopen positions generally to regulate blood flow direction in a humanpatient.

The hydrodynamic performance was measured prior to accelerated weartesting. The performance values were; EOA=1.88 cm² and regurgitantfraction=10.86%. No observable damage has been recorded duringdurability testing with the number of cycles nearing 100 million.

Example 4b

In exemplary embodiments, a heart valve was constructed with a valveframe, strain relief, sewing ring, and first three layers of compositematerial, as described above in Example 4a, and utilizing a leafletmaterial comprising a final composite having a mass per area of 11.80g/m², 9.74% fluoropolymer by weight, a dome burst strength of 17.3 KPa,and thickness of 5.78 μm after the coating steps.

Six additional layers of the composite material were wrapped around thecombined molds of FIG. 26 a with the membrane orientation as describedin Example 4a.

The assembly was molded, thermally processed, and trimmed as describedin Example 4a.

The final leaflet was comprised of 9.74% fluoropolymer by weight with athickness of 52.0 μm. Each leaflet had 9 layers of the compositematerial and a ratio of thickness/number of layers of 5.78 μm.

The hydrodynamic performance was measured prior to accelerated weartesting. The performance values were; EOA=2.05 cm² and regurgitantfraction=11.71%. Observable damage was recorded as frame detachmentduring durability testing at about 6 million cycles.

Example 4c

In exemplary embodiments, a heart valve was constructed with a valveframe that was laser machined and coated with FEP, as described above inExample 4a, and further provided with a cushion member attached to theperimeter of the frame adjacent to leaflets regions to minimize stressrelated to direct contact between the frame and the leaflet.

A 0.5 mm thick ePTFE fiber was helically wrapped onto a 1.143 mm mandrelwith a pitch that eliminated space between wraps. Two layers of 2.54 μmFEP film was wrapped over ePTFE fiber coils and was then subjected to athermal treatment by placing it in a forced air oven set to 320° C. forapproximately three minutes. The material was brought back to roomtemperature via air cooling at room temperature. The ePTFE fiber formeda contiguous coil tube once removed from the mandrel. The coiled tubewas cut into three 125 mm lengths and slit axially leaving only 5 mmintact as a coiled tube. Each of the three lengths was slid ontoFEP-coated frame to form the frame 1000′ having the cushion member 1030attached thereto for minimizing stress related to direct contact betweenthe frame 1000′ and the leaflet (not shown), as depicted in FIG. 31.

A valve frame, strain relief, sewing ring, leaflet material, and firstlayer of composite material were prepared, as described in Example 4a,encapsulating the cushion members and frame. The leaflet material wasprepared such that after the coating steps, the final composite had amass per area of 25.48 g/m², 8.91% fluoropolymer by weight, a dome burststrength of 31.7 KPa, and thickness of 13.08 μm.

Three additional layers of the composite material were wrapped aroundthe combined molds with the membrane orientation, as described inExample 4a.

The assembly was molded with cushion members, thermally processed, andtrimmed as described in Example 4a to form the final valve assembly1100′ having the frame 1000′ and the cushion member 1030 attachedthereto for minimizing stress related to direct contact between theframe 1000′ and the leaflets 1102′, as depicted in FIG. 32.

The final leaflet was comprised of 8.91% fluoropolymer by weight with athickness of 52.3 μm. Each leaflet had 4 layers of the composite and aratio of thickness/number of layers of 13.08 μm.

The hydrodynamic performance was not measured prior to accelerated weartesting. Observable damage was recorded as a hole formation in leafletduring durability testing at about 12.4 million cycles.

Example 5

In exemplary embodiments, a heart valve was constructed having a valveframe, strain relief, sewing ring, leaflet material, and first threelayers of composite material were prepared, as described in Example 4a,and further having the final leaflet described immediately below.

Fifteen additional layers of the composite material were wrapped aroundthe combined molds and with the membrane orientation as described inExample 4a.

The assembly was molded, thermally processed, and trimmed as describedin Example 4a.

The final leaflet was comprised of 9.74% fluoropolymer by weight with athickness of 98.3 μm. Each leaflet had 18 layers of the composite and aratio of thickness/number of layers of 5.46 μm.

The hydrodynamic performance was measured prior to accelerated weartesting. The performance values were; EOA=1.73 cm² and regurgitantfraction=11.71%. Observable damage was recorded as frame detachment andleaflet delamination during durability testing at about 100 millioncycles.

Example 6

In exemplary embodiments, a heart valve was constructed having a valveframe, cushion layer, strain relief, and sewing ring were prepared, asdescribed in Example 4c, and further having the final leaflet asdescribed immediately below.

A leaflet material was then prepared. The ePTFE membrane had a mass perarea of 0.31 g/m², a bubble point of 0.11 MPa, a thickness of about 127nm, a matrix tensile strength of 442.0 MPa in the longitudinal directionand 560.0 MPa in the transverse direction. This membrane was imbibedwith a fluoroelastomer as described in Example 4a. After the coatingsteps, the final ePTFE/fluoroelastomer or composite had a mass per areaof 1.04 g/m², 29.9% fluoropolymer by weight, a dome burst strength of9.9 KPa, and thickness of 0.52 μm.

Ninety-five layers of the composite was wrapped around the combinedmolds with the membrane oriented such that the matrix tensile strengthof 442 MPa is oriented axially and the elastomer rich side of themembrane facing toward the molds as described in Example 4a.

The assembly was molded, thermally processed, and trimmed as describedin Example 4a.

The final leaflet was comprised of 29.00% fluoropolymer by weight with athickness of 49.7 μm. Each leaflet had 95 layers of the composite and aratio of thickness/number of layers of 0.52 μm.

The hydrodynamic performance was measured prior to accelerated weartesting. The performance values were; EOA=2.19 cm² and regurgitantfraction=9.7%. No observable damage has been recorded during durabilitytesting.

Example 7

In other exemplary embodiments, a heart valve having polymeric leafletswas formed from a composite material having an expanded fluoropolymermembrane and an elastomeric material; joined to a metallic balloonexpandable stent frame; and was constructed according to the followingprocess:

A metallic balloon expandable stent frame was laser machined from alength of MP35N alloy annealed tube with an outside diameter of 26.00 mmand a wall thickness of 0.60 mm. A pattern was cut into the tube to forma cylindrically-shaped cut stent frame, also referred herein as asupport structure, as illustrated and generally indicated at 600 in theflat plane view of FIG. 6 a. The support structure 600, includes aplurality of small closed cells 602, a plurality of large closed cells604, and a plurality of leaflet closed cells 606. Note that one of theplurality of leaflet closed cells 606 appears as an open cell in FIG. 6Adue to the flat plane view. The cells 602, 604, 606 are generallyarranged along rows forming the annular shape of the support structure600.

The surface of the metallic frame was prepared as described in Example4a.

An ePTFE laminate was attached to the frame with a strain relief, in amanner similar to Example 4c. A 24 mm diameter cylindrical mandrel waswrapped with a single layer of Kapton® polyimide film (DuPont) and heldin place by an adhesive strip of Kapton® tape over the length of theoverlapping seam. Two layers of a substantially nonporous ePTFE having alayer of FEP disposed along an outer surface or side thereof was wrappedwith the FEP facing away from the mandrel surface; two layers of FEP,3.6 μm thick, were then wrapped over this. The metallic balloonexpandable stent frame was aligned coaxially over the wrapped mandrel.An additional two layers of FEP were wrapped over the stent on themandrel encapsulating the stent and strain relief. Two layers of asubstantially porous ePTFE were wrapped over the FEP followed by anadditional three layers of FEP wrapped over ePTFE. The entire assemblywas subjected to a thermal treatment by placing it in a forced air ovenset to 375° C. for twenty minutes and returned to room temperature byimmediate water quench upon removal from the oven. The laminate wastrimmed from regions of the frame to expose three windows for leafletattachment as depicted in FIG. 33 b.

A leaflet material was then prepared as described in Example 6. TheePTFE membrane had a mass per area of 0.29 g/m², a bubble point of 0.11MPa, a thickness of about 158 nm, a matrix tensile strength of 434.0 MPain the longitudinal direction and 646.0 MPa in the transverse direction.This membrane was imbibed with a fluoroelastomer as described in Example4a. After the coating process, the final ePTFE/fluoroelastomer compositehad a mass per area of 0.94 g/m², 30.3% fluoropolymer by weight, a domeburst strength of 4.14 KPa, and thickness of 0.44 μm.

Seventeen layers of the composite was wrapped around a 26 mm mandrel.The composite was oriented so that the matrix tensile strength of 434MPa was placed axially and the elastomer rich side of the membrane wasfacing toward the mandrel as described in Example 4a.

The subassembly containing the frame and strain relief was positioned onthe mandrel over the 17 layers. An additional 40 layers of compositewere wrapped, sandwiching the frame between both layers of compositecreating a total of 57 layers of composite. The mandrel, leaflet layers,and frame were covered by an impermeable layer and sealed at both ends.Using a pressure vessel, the assembly was heated to about 285° C. at 75psi for about 23 minutes and then allowed to cool to room temperaturewhile under pressure. The valve assembly was removed from the mandrel.The free edge of the leaflet was created by slicing the laminate in anarc at each of the three leaflet closed cells 606 on the frame freeingthe leaflet to open and close under fluid pressure. The leaflets weremolded into final shape using leaflet molding tools described in FIGS.5A-5B. Each of the leaflet molding tools was coaxially aligned to thebase tool to allow for a cover to be applied to the exterior of theframe.

A frame cover material was then prepared as described in Example 6. TheePTFE membrane had a mass per area of 0.86 g/m², a bubble point of 0.11MPa, a thickness of about 900 nm, a matrix tensile strength of 376.0 MPain the longitudinal direction and 501.0 MPa in the transverse direction.This membrane was imbibed with a fluoroelastomer as described in Example4a. After the coating process, the final ePTFE/fluoroelastomer compositehad a mass per area of 7.05 g/m², 14.1% fluoropolymer by weight, a domeburst strength of 13.1 KPa, and thickness of 3.28 μm.

Fifteen layers of the composite was wrapped around the valve frame whilebeing held in the shape set tooling. The composite was oriented so thatthe matrix tensile strength of 501 MPa was placed axially and theelastomer rich side of the membrane was facing toward the mandrel asdescribed in Example 4a. The final cover was comprised of 14.1%fluoropolymer by weight with a thickness of 49.2 μm.

The assembly was molded, thermally processed in an open atmosphereconvection oven at 250° C. for 1 hour. The valve was then removed fromthe molding tooling.

The final leaflet was comprised of 30.3% fluoropolymer by weight with athickness of 25.0 μm. Each leaflet had 57 layers of the composite and aratio of thickness/number of layers of 0.44 μm.

A plurality of longitudinally extending slits 1302 were formed in thetube 1300 resulting in the formation of a plurality of tabs 1304. Theslits can be formed by any suitable method known to those havingordinary skill in the art, such as by cutting with a blade.

The leaflet tools (not shown) were then slid out from underneath thetube 1300.

The three tabs 1304 created by forming the slits 1302 in the tube 1300were then fed inwardly through respective windows or cells formed in theframe, as depicted in FIG. 35. Each of the leaflet tools was coaxiallyaligned to the base tool to allow the inwardly fed tabs 1304 of the tube1300 from the previous step to be positioned and compressed between theleaflet tools and the female tri-leaflet mold surface configuration ofthe base tool. The combined tool assembly comprising the leaflet andbase tools, composite or leaflet material, and frame was then mountedbetween fixed and translational portions of a fixture. Both radial andaxial compression were applied by radially clamping the leaflet toolswhile simultaneously applying an axial load with the translational endof the fixture.

The assembly was molded, thermally processed, and trimmed as describedin Example 4a. The final valve assembly having the metallic balloonexpandable stent frame 600″, cushion members 1030″, and leaflets 704″ isshown in FIG. 36.

The final leaflet was comprised of 33.70% fluoropolymer by weight with athickness of 16.0 μm. Each leaflet had fifty layers of the composite anda ratio of thickness/number of layers of 0.32 μm.

The hydrodynamic performance was measured prior to use. The performancevalues were; EOA=2.0 cm² and regurgitant fraction=15.7%. No observabledamage has been recorded during durability testing.

Following construction and testing, the valve was sent to CarmedaCorporation (Carmeda AB, Stockholm Sweden) for heparin coating. Aftercoating, the completed valve was mounted on a balloon catheter andcrushed to a reduced diameter of 20French using a mechanical iriscrushing apparatus. The catheter-mounted valve was forwarded toSterigenics corp. (Salt lake city UT) for ethylene oxide sterilization.Using sterile technique the valve was inserted through a 20F sheath intothe surgically exposed iliac artery of an anesthetized 4 month old, 25Kg Ramboulet sheep. The catheter was advanced though the inferior venacava, through the right atrium and into the pulmonary artery trunk. Itwas deployed over the native pulmonary valve and actuated bypressurizing the balloon catheter to 4 atmospheres. Following angiogramand pressure measurements, the catheter was withdrawn and the animalrecovered. The valve, referred below as the explanted valve, remained inplace for one month, replacing the function of the native pulmonaryvalve.

The hydrodynamic performance of the explanted valve was measured afterexplant and compared with a control valve. The explanted valve wasexplanted, fixed in formalin solution, digested in sodium hydroxide,rinsed in ethanol, acetone and distilled water prior to testing. Thecontrol valve was a duplicate of the explanted valve that was compressedto the delivery diameter, redeployed on a balloon catheter and tested.Each valve was tested under both aortic and pulmonary flow conditions ina ViVitro real time tester. No degradation in hemodynamic performancewas observed.

The performance values for the explanted and control valves are listedin Table 5.

TABLE 5 Aortic conditions, 70 bpm, 5 liter/min, 125/89 peak bp PressureDrop EOA Closing (mmHg) (cm²) volume (ml) Control 8.9 1.99 4.12Explanted valve 6.8 2.12 2.69 Pulmonary conditions, 70 bpm, 5 liter/min,26/15 peak bp Control 9.5 1.82 2.25 Explanted 8.9 1.76 2.25

Example 8

In exemplary embodiments, a heart valve having polymeric leaflets joinedto a rigid metallic frame was constructed according to the followingprocess:

A valve support structure or frame 960 was laser cut from a length of316 stainless steel tube with an outside diameter of 25.4 mm and a wallthickness of 0.5 mm in the shape shown in FIG. 19. In the embodimentshown, the frame 960 extends axially between a bottom end 962 and anopposite top end defined generally by a plurality of axially extending,generally spire shaped posts 964 corresponding to the number of leafletsin the intended finished valve assembly (not shown). A parabolicallyshaped top edge 968 extends between adjacent posts 964. In the specificembodiment shown, three posts 964 and three top edges 968 form the topend of the frame 960. The corners of the frame that would be in contactwith the leaflet material were rounded using a rotary sander and handpolished. The frame was rinsed with water and then plasma cleaned usinga PT2000P plasma treatment system, Tri-Star Technologies, El Segundo,Calif., USA.

A cushion member is provided between at least a portion of the frame andat least a portion of the leaflet to minimize stress related to directcontact between the frame and the leaflet. A composite fiber of ePTFEand silicone was created by first imbibing an ePTFE membrane withsilicone MED-6215 (NuSil, Carpinteria, Calif., USA), slitting it to awidth of 25 mm, and rolling into a substantially round fiber. The ePTFEused in this fiber was tested in accordance with the methods describedin the Appendix. The ePTFE membrane had a bubble point of 217 KPa, athickness of 10 μm, a mass per area of 5.2 g/m², a porosity of 78%, amatrix tensile strength in one direction of 96 MPa, and a matrix tensilestrength of 55 MPa in an orthogonal direction. The composite fiber 966was wrapped around each of the posts 964 of the valve frame 960 as shownin FIG. 20.

A mandrel 970 was formed using stereolithography in a shape shown inFIG. 21. The mandrel 970 has a first end 972 and an opposite second end974, and extends longitudinally therebetween. The mandrel 970 has anouter surface 980 having three (two shown) generally arcuate, convexlobes 982, each generally for forming leaflets (not shown) of a finishedvalve assembly (not shown). The outer surface 980 also includes a frameseating area 984 for positioning the valve frame (960 in FIG. 19)relative to the lobes 982 prior to formation of the valve leaflets ontothe valve frame.

The mandrel 970 was then spray coated with a PTFE mold release agent.Four layers of ePTFE membrane were wrapped around the mandrel. The ePTFEmembrane was tested in accordance with the methods described in theAppendix. The ePTFE membrane had a mass per area of 0.57 g/m², aporosity of 90.4%, a thickness of about 2.5 μm, a bubble point of 458KPa, a matrix tensile strength of 339 MPa in the longitudinal directionand 257 MPa in the transverse direction. MED-6215 was wiped onto theePTFE and allowed to wet into and substantially fill the pores of theePTFE. Excess MED-6215 was blotted off and the valve frame 960 with thecomposite fiber 966 wrapped posts 964 was positioned on the mandrel 970along the frame seating area 984, as shown in FIG. 22. SiliconeMED-4720, NuSil, Carpinteria, Calif., USA was placed along the top edges968 of the frame 960 and along the posts 964 of the frame 960 to createa strain relief within the leaflet (not shown). Thirty additional layersof the same ePTFE were wrapped around the frame 960 and mandrel 970.Additional MED-6215 was wiped onto the ePTFE and allowed to wet into andsubstantially fill the pores of the ePTFE. 8 layers of ePTFE membranewere wrapped around the frame 960 and mandrel 970. The ePTFE used wastested in accordance with the methods described in the Appendix. TheePTFE membrane had a bubble point of 217 KPa, a thickness of 10 μm, amass per area of 5.2 g/m², a porosity of 78%, a matrix tensile strengthin one direction of 96 MPa, and a matrix tensile strength of 55 MPa inan orthogonal direction. These layers absorbed any excess siliconeduring the molding process and were removed after the silicone hadcured.

Silicone rubber forms (not shown) molded with one surface exactlymatching the inverse shape of the mandrel surface were previouslyfabricated for each of the 3 leaflet-forming features. These forms werespray coated with PTFE mold release and then mated to the matchingfeature of the mandrel. Approximately 50 wraps of an ePTFE fiber (notshown) were wound around the silicone forms to apply generally radialpressure to the valve against the mandrel.

This assembly was then placed in an oven at 100° C. for 1 hour to curethe silicone. After cooling, the fiber and silicone forms were removed,the 8 layers of blotter ePTFE were peeled away and discarded, and theresulting valve (not shown) was slid off of the mandrel. The posts weretrimmed using wire cutters and the excess length of leaflet material andexcess length of material at the base of the frame was carefully trimmedusing scissors to form a completed valve assembly, which is shown andgenerally indicated at 990 in FIG. 23. Thus, in one embodiment, thevalve assembly 990 was formed having the frame or support structure 960;a plurality of leaflets 992 supported on the support structure 960 andmovable between open and closed positions to regulate blood flow throughthe valve assembly 990; and a cushion member 1030 located between atleast a portion of the support structure 960 and at least a portion ofeach leaflet 992 to minimize stress in the leaflets due to the couplingand/or proximity of the leaflets to the support structure. In anotherembodiment, the cushion member is formed from a composite material withat least one fluoropolymer layer having a plurality of pores and anelastomer present in substantially all of the pores, as described above.

It should be appreciated that support structures other than asspecifically shown in the figures may be utilized. Further, cushionmembers may be utilized anywhere along the support structure asnecessary to minimize stress in the leaflets due to the coupling and/orproximity of the leaflets to the support structure. For example, cushionmember(s) may be coupled to the support structure along theparabolically shaped top edge.

It should also be appreciated that the cushion members may be formed assheets and wrapped around desired locations along the support structure,or be formed from fibers of various cross sectional shapes and sizes.

It should also be appreciated that the cushion members may be formed astubes and slid over the ends of the support structure, or be slitlongitudinally and positioned around the desired location along thesupport structure.

The leaflets of the complete valve assembly were measured and determinedto have an average thickness at the center of each leaflet of about 48μm.

The final leaflet was comprised of 24.00% fluoropolymer by weight with athickness of 48.0 μm. Each leaflet had 48 layers of the composite and aratio of thickness/number of layers of 1.07 μm.

The hydrodynamic performance was measured prior to accelerated weartesting. The performance values were; EOA=2.4 cm² and regurgitantfraction=12.5%. No observable damage has been recorded during durabilitytesting with the number of cycles of about 150 million.

The hydrodynamic performance of the valves described in Examples 4a, 4b,5, 6, 7, and 8 was characterized on a real-time pulse duplicator thatmeasured typical anatomical pressures and flows across the valve,generating an initial or “zero fatigue” set of data for that particularvalve assembly.

Following flow performance characterization, the valve assemblies werethen removed from the flow pulse duplicator system and placed into ahigh-rate fatigue or durability tester. The valves were continuouslymonitored to ensure they held pressure when closed and to assess whenany damage in the form of frame detachment, tears, holes, ordelamination occurred. Where appropriate, the hydrodynamic performanceof valves were again measured post durability testing at about 100million cycles and recorded.

The results of the performance characterizations are listed in FIG. 44,Table 6.

The data presented in Examples 4a, 4b, 4c, 5, 6, 7 & 8 and summarized inTables 4, 5 and 6 support the observation of general durability andhydrodynamic performance trends associated with different leafletconfigurations when thickness, percent fluoropolymer by weight, andnumber of layers are varied. The number of Examples presented supportthese observations by allowing comparisons to be made when differencesdue to frame type and cushion members are used in the individual valveconstruction.

Examples 4b and 4c are configurations where leaflet thickness andpercent fluoropolymer by weight are equal and illustrate that low layernumbers lead to reduced durability. The failure mode of Example 4b offrame detachment was mitigated by using a cushion member which in turndoubled the time to failure, however the failure mode switched fromframe detachment to hole formation within the leaflet. Both Examples 4aand 4b had durability failures well below what is acceptable.

Examples 4b and 5 provide a comparison where percent fluoropolymer byweight is held constant and a difference in layer number and thereforeleaflet thickness are measured. Both Examples have the same valveconstruction without the cushion members which have been shown above tomitigate frame detachment. The effect of doubling the number of layersfrom 9 to 18 and therefore increasing the leaflet thickness from about52 μm to about 98 μm improved the number of cycles to frame detachmentby nearly an order of magnitude from 12 million to 100 million.

Example 4a, which again is of similar construction to Examples 4b, whereleaflet thickness of about 50 μm is held constant and varying thepercent fluoropolymer by weight from about 10% for Example 4b to about30% for Example 4a enabled the creation of a thinner composite andtherefore many more layers (26) for the same leaflet thickness. Althoughsome free edge delamination has been observed for Example 4a near thehigh strain region of the triple point, the valve is still viable asdetermined by hydrodynamic characterization with 100 million cyclesaccrued as shown in Table 5.

In examples 6 and 7, the improved bending behavior of these thin andhigh layer configurations generally indicate that improved durabilityfollows when compared to lower layer number constructions due to thereduction in creases and wrinkles thought the duty cycle as illustratedin FIGS. 41A and 41B.

Additionally, Example 8 illustrates that similar durability can beachieved with different elastomers of high layer configurations asdemonstrated by Examples 6 and 7.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present embodimentswithout departing from the spirit or scope of the embodiments. Thus, itis intended that the present embodiments cover the modifications andvariations of this invention provided they come within the scope of theappended claims and their equivalents.

APPENDIX

As used in this application, matrix tensile strength refers to thetensile strength of a porous fluoropolymer specimen under specifiedconditions. The porosity of the specimen is accounted for by multiplyingthe tensile strength by the ratio of density of the polymer to thedensity of the specimen.

As used herein the term “membrane” refers to a porous fluoropolymerarticle, “composite” refers to imbibed porous fluoropolymers, and a“leaflet” is a component of an implantable article for regulating bloodflow direction. Leaflets of the present embodiments are one or morelayers of a composite.

The term “imbibe” used herein refers to any process used to at leastpartially fill pores with a secondary material.

For porous fluoropolymer leaflets having pores substantially filled withelastomer, the elastomer can be dissolved or degraded and rinsed awayusing an appropriate solvent in order to measure desired properties.

As the term “elastomer” is used herein it defines a polymer, mixture ofpolymers, or mixture of one or more polymers with one or morenon-polymeric components that has the ability to be stretched to atleast 1.3 times its original length and to retract rapidly toapproximately its original length when released. The term “elastomeric”is intended to describe a property whereby a polymer displays stretchand recovery properties similar to an elastomer, although notnecessarily to the same degree of stretch and/or recovery.

As the term “thermoplastic” is used herein it defines a polymer thatsoftens when exposed to heat and returns to its original condition whencooled to room temperature. Such a polymer can be made to soften, flowor take on new shapes, without significant degradation or alteration ofthe polymer's original condition, by the application of heat or heat andpressure. In contrast to a thermoplastic polymer, a “thermoset” polymeris hereby defined as a polymer that solidifies or “sets” irreversiblywhen cured. A determination of whether a polymer is a “thermoplastic”polymer within the meaning of the present embodiments can be made byslowly elevating the temperature of a stressed specimen and watching fordeformation. If the polymer can be made to soften, flow, or take on anew shape, without significant degradation or alteration of thepolymer's original chemical condition, then the polymer is considered tobe a thermoplastic. If only small amounts of material are available itmay be necessary to use a hot stage microscope for this determination.

One measure of the quality of a valve is the effective orifice area(EOA), which can be calculated as follows: EOA(cm²)=Q_(rms)/(51.6*(ΔP)^(1/2)) where Q_(rms) is the root mean squaresystolic/diastolic flow rate (cm³/s) and ΔP is the meansystolic/diastolic pressure drop (mmHg).

Another measure of the hydrodynamic performance of a valve is theregurgitant fraction, which is the amount of fluid or blood regurgitatedthrough the valve divided by the stroke volume.

As used in this application, the surface area per unit mass, expressedin units of m²/g, was measured using the Brunauer-Emmett-Teller (BET)method on a Coulter SA3100Gas Adsorption Analyzer, Beckman Coulter Inc.Fullerton Calif., USA. To perform the measurement, a sample was cut fromthe center of the expanded fluoropolymer membrane and placed into asmall sample tube. The mass of the sample was approximately 0.1 to 0.2g. The tube was placed into the Coulter SA-Prep Surface Area Outgasser(Model SA-Prep, P/n 5102014) from Beckman Coulter, Fullerton Calif., USAand purged at about 110° C. for about two hours with helium. The sampletube was then removed from the SA-Prep Outgasser and weighed. The sampletube was then placed into the SA3100 Gas adsorption Analyzer and the BETsurface area analysis was run in accordance with the instrumentinstructions using helium to calculate the free space and nitrogen asthe adsorbate gas.

Bubble point and mean flow pore size were measured according to thegeneral teachings of ASTM F31 6-03 using a capillary flow Porometer,Model CFP 1500AEXL from Porous Materials, Inc., Ithaca N.Y., USA. Thesample membrane was placed into the sample chamber and wet with SilWickSilicone Fluid (available from Porous Materials Inc.) having a surfacetension of about 20.1 dynes/cm. The bottom clamp of the sample chamberhad an about 2.54 cm diameter hole. Isopropyl alcohol was used as thetest fluid. Using the Capwin software version 7.73.012 the followingparameters were set as specified in the table below. As used herein,mean flow pore size and pore size are used interchangeably.

Parameter Set Point Maxflow (cm³/m) 200000 Bublflow (cm³/m) 100 F/PT(old bubltime) 50 Minbpress (PSI) 0 Zerotime (sec) 1 V2incr (cts) 10Preginc (cts) 1 Pulse delay(sec) 2 Maxpre (PSI) 500 Pulse width (sec)0.2 Mineqtime (sec) 30 Presslew (cts) 10 Flowslew (cts) 50 Eqiter 3Aveiter 20 Maxpdif (PSI) 0.1 Maxfdif (PSI) 50 Sartp (PSI) 1 Sartf(cm³/m) 500

Membrane thickness was measured by placing the membrane between the twoplates of a Käfer FZ1000/30 thickness snap gauge Käfer MessuhrenfabrikGmbH, Villingen-Schwenningen, Germany. The average of the threemeasurements was reported.

The presence of elastomer within the pores can be determined by severalmethods known to those having ordinary skill in the art, such as surfaceand/or cross section visual, or other analyses. These analyses can beperformed prior to and after the removal of elastomer from the leaflet.

Membrane samples were die cut to form rectangular sections about 2.54 cmby about 15.24 cm to measure the weight (using a Mettler-Toledoanalytical balance model AG204) and thickness (using a Käfer Fz1000/30snap gauge). Using these data, density was calculated with the followingformula: p=m/w*l*t, in which: ρ=density (g/cm³): m=mass (g), w=width(cm), l=length (cm), and t=thickness (cm. The average of threemeasurements was reported.

Tensile break load was measured using an INSTRON 122 tensile testmachine equipped with flat-faced grips and a 0.445 kN load cell. Thegauge length was about 5.08 cm and the cross-head speed was about 50.8cm/min. The sample dimensions were about 2.54 cm by about 15.24 cm. Forlongitudinal measurements, the longer dimension of the sample wasoriented in the highest strength direction. For the orthogonal MTSmeasurements, the larger dimension of the sample was orientedperpendicular to the highest strength direction. Each sample was weighedusing a Mettler Toledo Scale Model AG204, then the thickness measuredusing the Käfer FZ1000/30 snap gauge. The samples were then testedindividually on the tensile tester. Three different sections of eachsample were measured. The average of the three maximum loads (i.e., peakforce) measurements was reported. The longitudinal and transverse matrixtensile strengths (MTS) were calculated using the following equation:MTS=(maximum load/cross-section area)*(bulk density of PTFE)/(density ofthe porous membrane), wherein the bulk density of the PTFE was taken tobe about 2.2 g/cm³. Flexural stiffness was measured by following thegeneral procedures set forth in ASTM D790. Unless large test specimensare available, the test specimen must be scaled down. The testconditions were as follows. The leaflet specimens were measured on athree-point bending test apparatus employing sharp posts placedhorizontally about 5.08 mm from one another. An about 1.34 mm diametersteel bar weighing about 80 mg was used to cause deflection in the y(downward) direction, and the specimens were not restrained in the xdirection. The steel bar was slowly placed on the center point of themembrane specimen. After waiting about 5 minutes, the y deflection wasmeasured. Deflection of elastic beams supported as above can berepresented by: d=F*L³/48*El, where F (in Newtons) is the load appliedat the center of the beam length, L (meters), so L=½ distance betweensuspending posts, and El is the bending stiffness (Nm). From thisrelationship the value of El can be calculated. For a rectangularcross-section: I=t³*w/12, where I=cross-sectional moment of inertia,t=specimen thickness (meters), w=specimen width (meters). With thisrelationship, the average modulus of elasticity over the measured rangeof bending deflection can be calculated.

The average diameter of the fibrils was estimated by examining scanningelectron micrographs that were obtained having at a magnificationsuitable for showing numerous fibrils, such as the scanning electronmicroscopy (SEM) micrographs of FIGS. 7A-C. In the case of a compositematerial, it may be necessary to extract the elastomer or other materialthat may be filling the pores, by any suitable means, to expose thefibrils.

Surface Area Measurements

The surface area per unit mass (specific surface area), expressed inunits of m²/g, of the microporous polymer membrane was measured usingthe Brunauer-Emmett-Teller (BET) method on a Coulter SA3100 GasAdsorption Analyzer (Beckman Coulter Inc., Fullerton, Calif.). A samplewas cut from the center of the microporous polymer membrane sheet andplaced into a small sample tube. The mass of the sample wasapproximately 0.1 to 0.2 grams. The tube was placed into the CoulterSA-Prep Surface Area Outgasser, (Model SA-PREP, P/N 5102014) fromBeckman Coulter Inc., Fullerton, Calif. and purged at 110C for 2 hourswith helium. The sample tube was then removed from the SA-Prep Outgasserand weighed. The sample tube was then placed into the SA3100 GasAdsorption Analyzer and the BET surface area analysis was run inaccordance with the instrument instructions using helium to calculatethe free space and nitrogen as the adsorbate gas. A single measurementwas recorded for each sample.

It is useful to convert the specific surface area as expressed in unitsof m²/g to specific surface area expressed in units of m²/cc in order tocompare the specific surface areas of materials of different densities.To do so, multiply the specific surface area expressed in m²/g by thedensity of the sample material expressed in g/cc. The density of PTFEwas taken to be 2.2 g/cc and the density of polyethylene was taken to be0.98 g/cc.

What is claimed is:
 1. A valve, comprising: a support structure, and atleast one leaflet being supported on the support structure and movablebetween open and closed positions, each leaflet including a compositematerial comprising more than one fluoropolymer layer having a pluralityof pores and an elastomer present in substantially all of the pores ofthe more than one fluoropolymer layer, the leaflet having a ratio ofleaflet thickness (μm) to number of layers of fluoropolymer of less thanabout
 5. 2. The valve of claim 1, wherein the ratio of leaflet thickness(μm) to number of layers of fluoropolymer of less than about
 3. 3. Thevalve of claim 1, wherein the ratio of leaflet thickness (μm) to numberof layers of fluoropolymer of less than about
 1. 4. The valve of claim1, wherein the ratio of leaflet thickness (μm) to number of layers offluoropolymer of less than about 0.5.
 5. The valve of claim 1, whereinthe leaflet has at least 10 layers and a composite material comprisingless than about 50% fluoropolymer by weight.
 6. The valve of claim 5,wherein the leaflet has a thickness less than 100 μm.
 7. The valve ofclaim 6, wherein the leaflet has a bending modulus of less than about100 MPa.
 8. The valve of claim 1, wherein the pores have a pore sizethat is less than about 5 μm.
 9. The valve of claim 1, wherein the poreshave a pore size that is less than about 1 μm.
 10. The valve of claim 1,wherein the pores have a pore size that is less than about 0.10 μm. 11.The valve of claim 1, wherein the more than one fluoropolymer layercomprises fibrils, wherein a diameter of a majority of the fibrils isless than about 1 μm.
 12. The valve of claim 1, wherein the elastomer isa fluoroelastomer.
 13. The valve of claim 1, wherein the elastomer is aurethane.
 14. The valve of claim 1, wherein the elastomer is a TFE/PMVEcopolymer.
 15. The valve of claim 14, wherein the TFE/PMVE copolymercomprises essentially of between about 40 and 80 weight percentperfluoromethyl vinyl ether and complementally 60 and 20 weight percenttetrafluoroethylene.
 16. A valve, comprising: a support structure, andat least one leaflet being supported on the support structure andmovable between open and closed positions, each leaflet including acomposite material comprising more than one fluoropolymer layer having aplurality of pores and an elastomer present in substantially all of thepores of the more than one fluoropolymer layer, each leaflet having athickness of less than about 100 μm.
 17. The valve of claim 16, whereinthe leaflet includes at least 10 layers of the composite material. 18.The valve of claim 16, wherein a ratio of leaflet thickness (μm) tonumber of layers of fluoropolymer of less than about
 5. 19. The valve ofclaim 16, wherein a ratio of leaflet thickness (μm) to number of layersof fluoropolymer of less than about
 3. 20. The valve of claim 16,wherein a ratio of leaflet thickness (μm) to number of layers offluoropolymer of less than about
 1. 21. The valve of claim 16, wherein aratio of leaflet thickness (μm) to number of layers of fluoropolymer ofless than about 0.5.
 22. The valve of claim 16, wherein the leaflet hasat least 10 layers and a composite material comprising less than about50% fluoropolymer by weight.
 23. The valve of claim 22, wherein theleaflet has a thickness less than about 100 μm.
 24. The valve of claim23, wherein the leaflet has a bending modulus of less than about 100MPa.
 25. The valve of claim 16, wherein the pores have a pore size thatis less than about 5 μm.
 26. The valve of claim 16, wherein the poreshave a pore size that is less than about 1 μm.
 27. The valve of claim16, wherein the pores have a pore size that is less than about 0.10 μm.28. The valve of claim 16, wherein the more than one fluoropolymer layercomprises fibrils, wherein a diameter of a majority of the fibrils isless than about 1 μm.
 29. The valve of claim 16, wherein the elastomeris a fluoroelastomer.
 30. The valve of claim 16, wherein the elastomeris a urethane.
 31. The valve of claim 29, wherein the elastomer is aTFE/PMVE copolymer.
 32. The valve of claim 31, wherein the TFE/PMVEcopolymer comprises essentially of between about 40 and 80 weightpercent perfluoromethyl vinyl ether and complementally 60 and 20 weightpercent tetrafluoroethylene.
 33. A valve, comprising: a supportstructure including a leaflet support frame having a plurality ofsubstantially parabolically shaped top edges and posts, and a leafletbeing supported on each parabolically shaped top edge and posts, eachleaflet defining a free edge not coupled to the support structure, eachleaflet being movable between open and closed positions, each leafletincluding at least two layers of a composite material comprising morethan one fluoropolymer layer having a plurality of pores and anelastomer present in substantially all of the pores of the more than onefluoropolymer layer.
 34. The valve of claim 33, wherein at least onelayer of the at least two layers of a composite material is coupled toan inner surface of the support structure and wherein at least one layerof the at least two layers of a composite material is coupled to anouter surface of the support structure.
 35. The valve of claim 33,wherein each leaflet having a thickness of less than about 100 μm. 36.The valve of claim 33, wherein the leaflet includes at least 10 layersof the composite material.
 37. The valve of claim 33, wherein a ratio ofleaflet thickness (μm) to number of layers of fluoropolymer of less thanabout
 5. 38. The valve of claim 33, wherein a ratio of leaflet thickness(μm) to number of layers of fluoropolymer of less than about
 3. 39. Thevalve of claim 33, wherein a ratio of leaflet thickness (μm) to numberof layers of fluoropolymer of less than about
 1. 41. The valve of claim33, wherein a ratio of leaflet thickness (μm) to number of layers offluoropolymer of less than about 0.5.
 42. The valve of claim 33, whereinthe leaflet has at least 10 layers and a composite material comprisingless than about 50% fluoropolymer by weight.
 43. The valve of claim 42,wherein the leaflet has a thickness less than about 100 μm.
 44. Thevalve of claim 43, wherein the leaflet has a bending modulus of lessthan about 100 MPa.
 45. The valve of claim 33, wherein the pores have apore size that is less than about 5 μm.
 46. The valve of claim 33,wherein the pores have a pore size that is less than about 1 μm.
 47. Thevalve of claim 33, wherein the pores have a pore size that is less thanabout 0.10 μm.
 48. The valve of claim 33, wherein the more than onefluoropolymer layer comprises fibrils, wherein a diameter of a majorityof the fibrils is less than about 1 μm.
 49. The valve of claim 33,wherein the elastomer is a fluoroelastomer.
 50. The valve of claim 33,wherein the elastomer is a urethane.
 51. The valve of claim 49, whereinthe elastomer is a TFE/PMVE copolymer.
 52. The valve of claim 51,wherein the TFE/PMVE copolymer comprises essentially of between about 40and 80 weight percent perfluoromethyl vinyl ether and complementally 60and 20 weight percent tetrafluoroethylene.
 53. A method of forming aleaflet of an implantable article for regulating blood flow direction ina human patient, the method comprising: providing a composite materialhaving more than one fluoropolymer layer having a plurality of pores andan elastomer present in substantially all of the pores of the more thanone fluoropolymer layer; and bringing more than one layer of thecomposite material into contact with additional layers of the compositematerial by wrapping a sheet of the composite material with a startingand ending point defined as an axial seam adhered to itself.
 54. Themethod of claim 53, wherein wrapping a sheet of the composite materialcomprises wrapping a sheet of the composite material generally radiallywith the starting and ending point defined as the axial seam adhered toitself.
 55. The method of claim 53, wherein wrapping a sheet of thecomposite material comprises wrapping a sheet of the composite materialto a ratio of thickness (μm) to number of layers of fluoropolymer ofless than about
 5. 56. The method of claim 53, wherein providing acomposite material having more than one fluoropolymer layer having aplurality of pores comprises providing a composite material having morethan one fluoropolymer layer having a plurality of pores that have apore size that is less than about 5 μm.
 57. The method of claim 53,wherein providing a composite material having more than onefluoropolymer layer having a plurality of pores comprises providing acomposite material having more than one fluoropolymer layer having aplurality of pores that have a pore size that is less than about 1 μm.58. The method of claim 53, wherein providing a composite materialhaving more than one fluoropolymer layer having a plurality of porescomprises providing a composite material having more than onefluoropolymer layer having a plurality of pores that have a pore sizethat is less than about 0.10 μm.
 59. The method of claim 53, whereinproviding a composite material having more than one fluoropolymer layerhaving a plurality of pores comprises providing a composite materialhaving more than one fluoropolymer layer having a plurality of poresdefined by fibrils, wherein a diameter of a majority of the fibrils isless than about 1 μm.
 60. The method of claim 53, wherein providing acomposite material having an elastomer comprises providing a compositematerial having an elastomer that is a fluoroelastomer.
 61. The methodof claim 53, wherein providing a composite material having an elastomercomprises providing a composite material having an elastomer that is aTFE/PMVE copolymer.
 62. The method of claim 53, wherein providing acomposite material having an elastomer comprises providing a compositematerial having an elastomer that is a TFE/PMVE copolymer, wherein theTFE/PMVE copolymer comprises essentially of between about 40 and 80weight percent perfluoromethyl vinyl ether and complementally 60 and 20weight percent tetrafluoroethylene.
 63. The method of claim 53, whereinproviding a composite material having an elastomer comprises providing acomposite material having an elastomer that is a urethane.